WO2023131579A1 - Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of congenital muscular dystrophies - Google Patents
Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of congenital muscular dystrophies Download PDFInfo
- Publication number
- WO2023131579A1 WO2023131579A1 PCT/EP2023/000002 EP2023000002W WO2023131579A1 WO 2023131579 A1 WO2023131579 A1 WO 2023131579A1 EP 2023000002 W EP2023000002 W EP 2023000002W WO 2023131579 A1 WO2023131579 A1 WO 2023131579A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phthalazinedione
- dihydro
- amino
- pharmaceutically acceptable
- pharmaceutical composition
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 86
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 201000006815 congenital muscular dystrophy Diseases 0.000 title claims abstract description 63
- 150000003839 salts Chemical class 0.000 claims abstract description 75
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 59
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 claims abstract description 42
- RVJVDCVIJCBUTH-UHFFFAOYSA-M sodium;5-amino-2h-phthalazin-3-ide-1,4-dione Chemical compound [Na+].O=C1N[N-]C(=O)C2=C1C(N)=CC=C2 RVJVDCVIJCBUTH-UHFFFAOYSA-M 0.000 claims abstract description 28
- 102100022745 Laminin subunit alpha-2 Human genes 0.000 claims description 45
- -1 coatings Substances 0.000 claims description 41
- 239000000126 substance Substances 0.000 claims description 36
- 239000013543 active substance Substances 0.000 claims description 32
- 239000006199 nebulizer Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000000872 buffer Substances 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 18
- 239000000843 powder Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 239000003826 tablet Substances 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 239000000499 gel Substances 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- 239000011230 binding agent Substances 0.000 claims description 9
- 239000003623 enhancer Substances 0.000 claims description 9
- 239000000839 emulsion Substances 0.000 claims description 8
- 239000000017 hydrogel Substances 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 8
- 239000003963 antioxidant agent Substances 0.000 claims description 7
- 239000003086 colorant Substances 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 239000008187 granular material Substances 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 7
- 239000006188 syrup Substances 0.000 claims description 7
- 235000020357 syrup Nutrition 0.000 claims description 7
- 239000000969 carrier Substances 0.000 claims description 6
- 238000000576 coating method Methods 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 6
- 239000003995 emulsifying agent Substances 0.000 claims description 6
- 235000003599 food sweetener Nutrition 0.000 claims description 6
- 239000007903 gelatin capsule Substances 0.000 claims description 6
- 239000002594 sorbent Substances 0.000 claims description 6
- 239000003381 stabilizer Substances 0.000 claims description 6
- 239000006190 sub-lingual tablet Substances 0.000 claims description 6
- 239000003765 sweetening agent Substances 0.000 claims description 6
- 229920000858 Cyclodextrin Polymers 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 239000003921 oil Substances 0.000 claims description 5
- 238000010586 diagram Methods 0.000 claims description 4
- 239000008298 dragée Substances 0.000 claims description 4
- 239000006260 foam Substances 0.000 claims description 4
- 239000002502 liposome Substances 0.000 claims description 4
- 239000003605 opacifier Substances 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 239000004267 EU approved acidity regulator Substances 0.000 claims description 3
- 239000001692 EU approved anti-caking agent Substances 0.000 claims description 3
- 239000002535 acidifier Substances 0.000 claims description 3
- 229940095602 acidifiers Drugs 0.000 claims description 3
- 239000002518 antifoaming agent Substances 0.000 claims description 3
- 239000004088 foaming agent Substances 0.000 claims description 3
- 239000003752 hydrotrope Substances 0.000 claims description 3
- 239000006072 paste Substances 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- 235000013616 tea Nutrition 0.000 claims description 3
- 239000002562 thickening agent Substances 0.000 claims description 3
- 241000195940 Bryophyta Species 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000007933 dermal patch Substances 0.000 claims description 2
- 239000010408 film Substances 0.000 claims description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 claims description 2
- 229940040145 liniment Drugs 0.000 claims description 2
- 239000000865 liniment Substances 0.000 claims description 2
- 239000006210 lotion Substances 0.000 claims description 2
- 239000000693 micelle Substances 0.000 claims description 2
- 235000011929 mousse Nutrition 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000007940 sugar coated tablet Substances 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims description 2
- 239000007930 transdermal spray Substances 0.000 claims description 2
- 238000002050 diffraction method Methods 0.000 claims 1
- 229940112141 dry powder inhaler Drugs 0.000 claims 1
- 230000002500 effect on skin Effects 0.000 claims 1
- 238000001990 intravenous administration Methods 0.000 claims 1
- 239000007937 lozenge Substances 0.000 claims 1
- 229940071648 metered dose inhaler Drugs 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 53
- 238000000034 method Methods 0.000 abstract description 27
- 239000003862 glucocorticoid Substances 0.000 abstract description 25
- 238000009472 formulation Methods 0.000 abstract description 20
- 210000003205 muscle Anatomy 0.000 description 79
- 235000002639 sodium chloride Nutrition 0.000 description 62
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 108090000623 proteins and genes Proteins 0.000 description 25
- 241000699670 Mus sp. Species 0.000 description 23
- 230000035772 mutation Effects 0.000 description 23
- 201000010099 disease Diseases 0.000 description 22
- 239000000443 aerosol Substances 0.000 description 19
- 208000024891 symptom Diseases 0.000 description 19
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 16
- 229960005205 prednisolone Drugs 0.000 description 16
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 16
- 241000699666 Mus <mouse, genus> Species 0.000 description 15
- 108010069091 Dystrophin Proteins 0.000 description 14
- 229960001145 deflazacort Drugs 0.000 description 14
- FBHSPRKOSMHSIF-GRMWVWQJSA-N deflazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O FBHSPRKOSMHSIF-GRMWVWQJSA-N 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 11
- 208000010428 Muscle Weakness Diseases 0.000 description 11
- 206010028372 Muscular weakness Diseases 0.000 description 11
- 229920002472 Starch Polymers 0.000 description 11
- 230000037396 body weight Effects 0.000 description 11
- 150000004677 hydrates Chemical class 0.000 description 11
- 238000002663 nebulization Methods 0.000 description 11
- 239000012453 solvate Substances 0.000 description 11
- 235000019698 starch Nutrition 0.000 description 11
- 239000007924 injection Substances 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000002245 particle Substances 0.000 description 10
- 239000008107 starch Substances 0.000 description 10
- 206010028289 Muscle atrophy Diseases 0.000 description 9
- 201000006793 Walker-Warburg syndrome Diseases 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 201000006938 muscular dystrophy Diseases 0.000 description 9
- 230000000750 progressive effect Effects 0.000 description 9
- 229940032147 starch Drugs 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 8
- 102100032341 PCNA-interacting partner Human genes 0.000 description 8
- 101710196737 PCNA-interacting partner Proteins 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 230000009286 beneficial effect Effects 0.000 description 8
- 239000001768 carboxy methyl cellulose Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 235000014113 dietary fatty acids Nutrition 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 229930195729 fatty acid Natural products 0.000 description 8
- 239000000194 fatty acid Substances 0.000 description 8
- 239000008297 liquid dosage form Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 201000000585 muscular atrophy Diseases 0.000 description 8
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 8
- 229920001223 polyethylene glycol Polymers 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 210000002027 skeletal muscle Anatomy 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 239000001993 wax Substances 0.000 description 8
- 102000007547 Laminin Human genes 0.000 description 7
- 108010085895 Laminin Proteins 0.000 description 7
- 230000002411 adverse Effects 0.000 description 7
- 235000010443 alginic acid Nutrition 0.000 description 7
- 229920000615 alginic acid Polymers 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 239000001913 cellulose Substances 0.000 description 7
- 235000011187 glycerol Nutrition 0.000 description 7
- 230000006872 improvement Effects 0.000 description 7
- YSZIOXAEADAJLX-UHFFFAOYSA-N phthalazine-1,4-dione Chemical class C1=CC=C2C(=O)N=NC(=O)C2=C1 YSZIOXAEADAJLX-UHFFFAOYSA-N 0.000 description 7
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 7
- 230000000241 respiratory effect Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 229940037128 systemic glucocorticoids Drugs 0.000 description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical class CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 201000006935 Becker muscular dystrophy Diseases 0.000 description 6
- 102000001039 Dystrophin Human genes 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 6
- 208000021642 Muscular disease Diseases 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000006708 antioxidants Nutrition 0.000 description 6
- 235000012216 bentonite Nutrition 0.000 description 6
- 230000007812 deficiency Effects 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 229960004618 prednisone Drugs 0.000 description 6
- 229920001817 Agar Polymers 0.000 description 5
- 241000416162 Astragalus gummifer Species 0.000 description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 5
- 208000037141 Congenital muscular dystrophy, Fukuyama type Diseases 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 5
- 208000013135 GNE myopathy Diseases 0.000 description 5
- 241000282414 Homo sapiens Species 0.000 description 5
- 101001003584 Homo sapiens Prelamin-A/C Proteins 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 201000009623 Myopathy Diseases 0.000 description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 102100026531 Prelamin-A/C Human genes 0.000 description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 5
- 235000021355 Stearic acid Nutrition 0.000 description 5
- 229920001615 Tragacanth Polymers 0.000 description 5
- 208000006269 X-Linked Bulbo-Spinal Atrophy Diseases 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 235000010419 agar Nutrition 0.000 description 5
- MTHSVFCYNBDYFN-UHFFFAOYSA-N anhydrous diethylene glycol Natural products OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 5
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 5
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 5
- 239000004359 castor oil Substances 0.000 description 5
- 235000019438 castor oil Nutrition 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 210000003414 extremity Anatomy 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 208000025855 muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Diseases 0.000 description 5
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 5
- 229960004063 propylene glycol Drugs 0.000 description 5
- 235000013772 propylene glycol Nutrition 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 5
- 239000008117 stearic acid Substances 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 235000010487 tragacanth Nutrition 0.000 description 5
- 239000000196 tragacanth Substances 0.000 description 5
- 229940116362 tragacanth Drugs 0.000 description 5
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 4
- ZFMSMUAANRJZFM-UHFFFAOYSA-N Estragole Chemical compound COC1=CC=C(CC=C)C=C1 ZFMSMUAANRJZFM-UHFFFAOYSA-N 0.000 description 4
- 208000037149 Facioscapulohumeral dystrophy Diseases 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 4
- 102000003964 Histone deacetylase Human genes 0.000 description 4
- 108090000353 Histone deacetylase Proteins 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 102100033341 N-acetylmannosamine kinase Human genes 0.000 description 4
- 201000009110 Oculopharyngeal muscular dystrophy Diseases 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 description 4
- 239000004365 Protease Substances 0.000 description 4
- 208000022583 Qualitative or quantitative defects of dysferlin Diseases 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000003510 anti-fibrotic effect Effects 0.000 description 4
- 239000000440 bentonite Substances 0.000 description 4
- 229910000278 bentonite Inorganic materials 0.000 description 4
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 description 4
- 235000010216 calcium carbonate Nutrition 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- QMVPMAAFGQKVCJ-UHFFFAOYSA-N citronellol Chemical compound OCCC(C)CCC=C(C)C QMVPMAAFGQKVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 208000008570 facioscapulohumeral muscular dystrophy Diseases 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 235000010449 maltitol Nutrition 0.000 description 4
- 239000000845 maltitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 210000004379 membrane Anatomy 0.000 description 4
- 229940041616 menthol Drugs 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 235000010981 methylcellulose Nutrition 0.000 description 4
- 239000001923 methylcellulose Substances 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 4
- 208000002086 myofibrillar myopathy Diseases 0.000 description 4
- 239000006186 oral dosage form Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 238000000554 physical therapy Methods 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 238000003825 pressing Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229940083542 sodium Drugs 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 235000015424 sodium Nutrition 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 3
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 3
- 208000037663 Best vitelliform macular dystrophy Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 3
- 102100036912 Desmin Human genes 0.000 description 3
- 108010044052 Desmin Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 201000006813 Fukuyama congenital muscular dystrophy Diseases 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- 101001023021 Homo sapiens LIM domain-binding protein 3 Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 3
- 102100035112 LIM domain-binding protein 3 Human genes 0.000 description 3
- 239000000232 Lipid Bilayer Substances 0.000 description 3
- 102000004472 Myostatin Human genes 0.000 description 3
- 108010056852 Myostatin Proteins 0.000 description 3
- 206010068871 Myotonic dystrophy Diseases 0.000 description 3
- DBXNUXBLKRLWFA-UHFFFAOYSA-N N-(2-acetamido)-2-aminoethanesulfonic acid Chemical compound NC(=O)CNCCS(O)(=O)=O DBXNUXBLKRLWFA-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 3
- 235000011613 Pinus brutia Nutrition 0.000 description 3
- 241000018646 Pinus brutia Species 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 102100031754 Ribitol-5-phosphate transferase FKTN Human genes 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 3
- 201000006814 Ullrich congenital muscular dystrophy Diseases 0.000 description 3
- 240000008042 Zea mays Species 0.000 description 3
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- 235000012665 annatto Nutrition 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 229960000541 cetyl alcohol Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 235000005822 corn Nutrition 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical class C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 210000005045 desmin Anatomy 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 239000001177 diphosphate Substances 0.000 description 3
- 235000013804 distarch phosphate Nutrition 0.000 description 3
- 239000001245 distarch phosphate Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 235000011087 fumaric acid Nutrition 0.000 description 3
- 229960002598 fumaric acid Drugs 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 102000006495 integrins Human genes 0.000 description 3
- 108010044426 integrins Proteins 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 230000004065 mitochondrial dysfunction Effects 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 208000011042 muscle-eye-brain disease Diseases 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 3
- 235000012658 paprika extract Nutrition 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 210000003800 pharynx Anatomy 0.000 description 3
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 229960003975 potassium Drugs 0.000 description 3
- 235000019814 powdered cellulose Nutrition 0.000 description 3
- 229920003124 powdered cellulose Polymers 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229960002052 salbutamol Drugs 0.000 description 3
- 210000003296 saliva Anatomy 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 235000010413 sodium alginate Nutrition 0.000 description 3
- 239000000661 sodium alginate Substances 0.000 description 3
- 229940005550 sodium alginate Drugs 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 3
- 229940001584 sodium metabisulfite Drugs 0.000 description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 239000013589 supplement Substances 0.000 description 3
- 230000009747 swallowing Effects 0.000 description 3
- 238000002636 symptomatic treatment Methods 0.000 description 3
- 150000003505 terpenes Chemical class 0.000 description 3
- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical compound COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 3
- 239000001069 triethyl citrate Substances 0.000 description 3
- 235000013769 triethyl citrate Nutrition 0.000 description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 3
- 208000034373 type A muscular dystrophy-dystroglycanopathy Diseases 0.000 description 3
- ZYTXTXAMMDTYDQ-DGEXFFLYSA-N vamorolone Chemical compound C([C@H]12)CC3=CC(=O)C=C[C@]3(C)C1=CC[C@@]1(C)[C@H]2C[C@@H](C)[C@]1(O)C(=O)CO ZYTXTXAMMDTYDQ-DGEXFFLYSA-N 0.000 description 3
- 229950011597 vamorolone Drugs 0.000 description 3
- 208000020938 vitelliform macular dystrophy 2 Diseases 0.000 description 3
- 239000000341 volatile oil Substances 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- 229920001285 xanthan gum Polymers 0.000 description 3
- 235000010493 xanthan gum Nutrition 0.000 description 3
- 239000000230 xanthan gum Substances 0.000 description 3
- 229940082509 xanthan gum Drugs 0.000 description 3
- JGQFVRIQXUFPAH-UHFFFAOYSA-N α-citronellol Chemical compound OCCC(C)CCCC(C)=C JGQFVRIQXUFPAH-UHFFFAOYSA-N 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- KVHQNWGLVVERFR-ACMTZBLWSA-N (3s)-3-amino-4-[[(2s)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoic acid;6-methyl-2,2-dioxooxathiazin-4-one Chemical compound CC1=CC(=O)[NH2+]S(=O)(=O)O1.[O-]C(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 KVHQNWGLVVERFR-ACMTZBLWSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- ZCHHRLHTBGRGOT-SNAWJCMRSA-N (E)-hex-2-en-1-ol Chemical compound CCC\C=C\CO ZCHHRLHTBGRGOT-SNAWJCMRSA-N 0.000 description 2
- QMVPMAAFGQKVCJ-SNVBAGLBSA-N (R)-(+)-citronellol Natural products OCC[C@H](C)CCC=C(C)C QMVPMAAFGQKVCJ-SNVBAGLBSA-N 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- IAIHUHQCLTYTSF-UHFFFAOYSA-N 2,2,4-trimethylbicyclo[2.2.1]heptan-3-ol Chemical compound C1CC2(C)C(O)C(C)(C)C1C2 IAIHUHQCLTYTSF-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- OOUGLTULBSNHNF-UHFFFAOYSA-N 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(C=2N=C(ON=2)C=2C(=CC=CC=2)F)=C1 OOUGLTULBSNHNF-UHFFFAOYSA-N 0.000 description 2
- GTLGHKNKLRZSMO-UHFFFAOYSA-N 4-(3-hydroxybutyl)-2-methoxyphenol Chemical compound COC1=CC(CCC(C)O)=CC=C1O GTLGHKNKLRZSMO-UHFFFAOYSA-N 0.000 description 2
- HUDPLKWXRLNSPC-UHFFFAOYSA-N 4-aminophthalhydrazide Chemical group O=C1NNC(=O)C=2C1=CC(N)=CC=2 HUDPLKWXRLNSPC-UHFFFAOYSA-N 0.000 description 2
- 101710190981 50S ribosomal protein L6 Proteins 0.000 description 2
- SERLAGPUMNYUCK-YJOKQAJESA-N 6-O-alpha-D-glucopyranosyl-D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-YJOKQAJESA-N 0.000 description 2
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 239000007991 ACES buffer Substances 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- 239000004114 Ammonium polyphosphate Substances 0.000 description 2
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000004385 Aspartame-acesulfame salt Substances 0.000 description 2
- 102100027954 BAG family molecular chaperone regulator 3 Human genes 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 2
- 239000004140 Calcium stearoyl fumarate Substances 0.000 description 2
- 240000004160 Capsicum annuum Species 0.000 description 2
- 235000008534 Capsicum annuum var annuum Nutrition 0.000 description 2
- BAVONGHXFVOKBV-UHFFFAOYSA-N Carveol Chemical compound CC(=C)C1CC=C(C)C(O)C1 BAVONGHXFVOKBV-UHFFFAOYSA-N 0.000 description 2
- 208000002177 Cataract Diseases 0.000 description 2
- 240000003538 Chamaemelum nobile Species 0.000 description 2
- 235000007866 Chamaemelum nobile Nutrition 0.000 description 2
- 241001672694 Citrus reticulata Species 0.000 description 2
- 240000000560 Citrus x paradisi Species 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- KRCZYMFUWVJCLI-UHFFFAOYSA-N Dihydrocarveol Chemical compound CC1CCC(C(C)=C)CC1O KRCZYMFUWVJCLI-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 102100035425 DnaJ homolog subfamily B member 6 Human genes 0.000 description 2
- 102100021158 Double homeobox protein 4 Human genes 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- WEEGYLXZBRQIMU-UHFFFAOYSA-N Eucalyptol Chemical compound C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 description 2
- 244000166124 Eucalyptus globulus Species 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 208000028782 Hereditary disease Diseases 0.000 description 2
- 101000968549 Homo sapiens Double homeobox protein 4 Proteins 0.000 description 2
- 101000846336 Homo sapiens Ribitol-5-phosphate transferase FKTN Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000026350 Inborn Genetic disease Diseases 0.000 description 2
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 229920000161 Locust bean gum Polymers 0.000 description 2
- 239000007993 MOPS buffer Substances 0.000 description 2
- 235000007232 Matricaria chamomilla Nutrition 0.000 description 2
- 208000024556 Mendelian disease Diseases 0.000 description 2
- 235000006679 Mentha X verticillata Nutrition 0.000 description 2
- 244000246386 Mentha pulegium Species 0.000 description 2
- 235000016257 Mentha pulegium Nutrition 0.000 description 2
- 235000002899 Mentha suaveolens Nutrition 0.000 description 2
- 235000004357 Mentha x piperita Nutrition 0.000 description 2
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 2
- PFYHAAAQPNMZHO-UHFFFAOYSA-N Methyl 2-methoxybenzoate Chemical compound COC(=O)C1=CC=CC=C1OC PFYHAAAQPNMZHO-UHFFFAOYSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 206010028311 Muscle hypertrophy Diseases 0.000 description 2
- 102100038894 Myotilin Human genes 0.000 description 2
- 101710100281 Myotilin Proteins 0.000 description 2
- 108010052185 Myotonin-Protein Kinase Proteins 0.000 description 2
- 102100022437 Myotonin-protein kinase Human genes 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 description 2
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 108020004485 Nonsense Codon Proteins 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 239000007990 PIPES buffer Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 206010033557 Palpitations Diseases 0.000 description 2
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 235000012550 Pimpinella anisum Nutrition 0.000 description 2
- 240000004760 Pimpinella anisum Species 0.000 description 2
- 244000203593 Piper nigrum Species 0.000 description 2
- 235000008184 Piper nigrum Nutrition 0.000 description 2
- 101710139641 Polyadenylate-binding protein 2 Proteins 0.000 description 2
- 102100039427 Polyadenylate-binding protein 2 Human genes 0.000 description 2
- 229920001100 Polydextrose Polymers 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000004139 Sodium stearoyl fumarate Substances 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 2
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 2
- 208000003954 Spinal Muscular Atrophies of Childhood Diseases 0.000 description 2
- REVZBRXEBPWDRA-UHFFFAOYSA-N Stearyl citrate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)CC(O)(C(O)=O)CC(O)=O REVZBRXEBPWDRA-UHFFFAOYSA-N 0.000 description 2
- 239000004138 Stearyl citrate Substances 0.000 description 2
- 235000015125 Sterculia urens Nutrition 0.000 description 2
- 240000001058 Sterculia urens Species 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 235000016639 Syzygium aromaticum Nutrition 0.000 description 2
- 244000223014 Syzygium aromaticum Species 0.000 description 2
- 239000007994 TES buffer Substances 0.000 description 2
- MOYAFQVGZZPNRA-UHFFFAOYSA-N Terpinolene Chemical compound CC(C)=C1CCC(C)=CC1 MOYAFQVGZZPNRA-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 108010075653 Utrophin Proteins 0.000 description 2
- 102000011856 Utrophin Human genes 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 235000013770 acetylated oxidized starch Nutrition 0.000 description 2
- 239000001073 acetylated oxidized starch Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- ANVAOWXLWRTKGA-XHGAXZNDSA-N all-trans-alpha-carotene Chemical compound CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1C(C)=CCCC1(C)C ANVAOWXLWRTKGA-XHGAXZNDSA-N 0.000 description 2
- 229940087168 alpha tocopherol Drugs 0.000 description 2
- IGODOXYLBBXFDW-UHFFFAOYSA-N alpha-Terpinyl acetate Chemical compound CC(=O)OC(C)(C)C1CCC(C)=CC1 IGODOXYLBBXFDW-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 229920001276 ammonium polyphosphate Polymers 0.000 description 2
- 235000019826 ammonium polyphosphate Nutrition 0.000 description 2
- 239000001670 anatto Substances 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 230000000181 anti-adherent effect Effects 0.000 description 2
- 239000003911 antiadherent Substances 0.000 description 2
- 229940125681 anticonvulsant agent Drugs 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000000074 antisense oligonucleotide Substances 0.000 description 2
- 238000012230 antisense oligonucleotides Methods 0.000 description 2
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 2
- 235000019413 aspartame-acesulfame salt Nutrition 0.000 description 2
- 229960003995 ataluren Drugs 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 229960004365 benzoic acid Drugs 0.000 description 2
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- UAHWPYUMFXYFJY-UHFFFAOYSA-N beta-myrcene Chemical compound CC(C)=CCCC(=C)C=C UAHWPYUMFXYFJY-UHFFFAOYSA-N 0.000 description 2
- LLEMOWNGBBNAJR-UHFFFAOYSA-N biphenyl-2-ol Chemical compound OC1=CC=CC=C1C1=CC=CC=C1 LLEMOWNGBBNAJR-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 235000010338 boric acid Nutrition 0.000 description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 2
- 235000011092 calcium acetate Nutrition 0.000 description 2
- 239000001639 calcium acetate Substances 0.000 description 2
- 229960005147 calcium acetate Drugs 0.000 description 2
- 235000010410 calcium alginate Nutrition 0.000 description 2
- 239000000648 calcium alginate Substances 0.000 description 2
- 229960002681 calcium alginate Drugs 0.000 description 2
- 239000001362 calcium malate Substances 0.000 description 2
- 235000019827 calcium polyphosphate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 235000019332 calcium stearoyl fumarate Nutrition 0.000 description 2
- PUYPFNCPLLJNCH-VFUQPONKSA-L calcium;(e)-4-octadecanoyloxy-4-oxobut-2-enoate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC(=O)OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(=O)OC(=O)\C=C\C([O-])=O PUYPFNCPLLJNCH-VFUQPONKSA-L 0.000 description 2
- FDSDTBUPSURDBL-LOFNIBRQSA-N canthaxanthin Chemical compound CC=1C(=O)CCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C(=O)CCC1(C)C FDSDTBUPSURDBL-LOFNIBRQSA-N 0.000 description 2
- 235000013736 caramel Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 229960001631 carbomer Drugs 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229960004424 carbon dioxide Drugs 0.000 description 2
- 235000012730 carminic acid Nutrition 0.000 description 2
- 239000004106 carminic acid Substances 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 230000001364 causal effect Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229960005233 cineole Drugs 0.000 description 2
- NEHNMFOYXAPHSD-UHFFFAOYSA-N citronellal Chemical compound O=CCC(C)CCC=C(C)C NEHNMFOYXAPHSD-UHFFFAOYSA-N 0.000 description 2
- 235000000484 citronellol Nutrition 0.000 description 2
- JOZKFWLRHCDGJA-UHFFFAOYSA-N citronellol acetate Chemical compound CC(=O)OCCC(C)CCC=C(C)C JOZKFWLRHCDGJA-UHFFFAOYSA-N 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- KSMVZQYAVGTKIV-UHFFFAOYSA-N decanal Chemical compound CCCCCCCCCC=O KSMVZQYAVGTKIV-UHFFFAOYSA-N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 235000015872 dietary supplement Nutrition 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- OSVXSBDYLRYLIG-UHFFFAOYSA-N dioxidochlorine(.) Chemical compound O=Cl=O OSVXSBDYLRYLIG-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- OPGYRRGJRBEUFK-UHFFFAOYSA-L disodium;diacetate Chemical compound [Na+].[Na+].CC([O-])=O.CC([O-])=O OPGYRRGJRBEUFK-UHFFFAOYSA-L 0.000 description 2
- 201000009338 distal myopathy Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 2
- CBOQJANXLMLOSS-UHFFFAOYSA-N ethyl vanillin Chemical compound CCOC1=CC(C=O)=CC=C1O CBOQJANXLMLOSS-UHFFFAOYSA-N 0.000 description 2
- RRAFCDWBNXTKKO-UHFFFAOYSA-N eugenol Chemical compound COC1=CC(CC=C)=CC=C1O RRAFCDWBNXTKKO-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 229940050411 fumarate Drugs 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- HIGQPQRQIQDZMP-UHFFFAOYSA-N geranil acetate Natural products CC(C)=CCCC(C)=CCOC(C)=O HIGQPQRQIQDZMP-UHFFFAOYSA-N 0.000 description 2
- HIGQPQRQIQDZMP-DHZHZOJOSA-N geranyl acetate Chemical compound CC(C)=CCC\C(C)=C\COC(C)=O HIGQPQRQIQDZMP-DHZHZOJOSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Chemical compound NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 2
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 210000001624 hip Anatomy 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 235000001050 hortel pimenta Nutrition 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 210000002414 leg Anatomy 0.000 description 2
- CDOSHBSSFJOMGT-UHFFFAOYSA-N linalool Chemical compound CC(C)=CCCC(C)(O)C=C CDOSHBSSFJOMGT-UHFFFAOYSA-N 0.000 description 2
- UWKAYLJWKGQEPM-LBPRGKRZSA-N linalyl acetate Chemical compound CC(C)=CCC[C@](C)(C=C)OC(C)=O UWKAYLJWKGQEPM-LBPRGKRZSA-N 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 235000010420 locust bean gum Nutrition 0.000 description 2
- 239000000711 locust bean gum Substances 0.000 description 2
- 238000011866 long-term treatment Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 229940098895 maleic acid Drugs 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 229940099690 malic acid Drugs 0.000 description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 2
- 229940035436 maltitol Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- UODXCYZDMHPIJE-UHFFFAOYSA-N menthanol Chemical compound CC1CCC(C(C)(C)O)CC1 UODXCYZDMHPIJE-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- QCAWEPFNJXQPAN-UHFFFAOYSA-N methoxyfenozide Chemical compound COC1=CC=CC(C(=O)NN(C(=O)C=2C=C(C)C=C(C)C=2)C(C)(C)C)=C1C QCAWEPFNJXQPAN-UHFFFAOYSA-N 0.000 description 2
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 235000010935 mono and diglycerides of fatty acids Nutrition 0.000 description 2
- 210000002161 motor neuron Anatomy 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 230000020763 muscle atrophy Effects 0.000 description 2
- 230000012042 muscle hypertrophy Effects 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 210000001087 myotubule Anatomy 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- GYHFUZHODSMOHU-UHFFFAOYSA-N nonanal Chemical compound CCCCCCCCC=O GYHFUZHODSMOHU-UHFFFAOYSA-N 0.000 description 2
- 230000037434 nonsense mutation Effects 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000001688 paprika extract Substances 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000001814 pectin Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 210000004197 pelvis Anatomy 0.000 description 2
- RUMOYJJNUMEFDD-UHFFFAOYSA-N perillyl aldehyde Chemical compound CC(=C)C1CCC(C=O)=CC1 RUMOYJJNUMEFDD-UHFFFAOYSA-N 0.000 description 2
- 230000000737 periodic effect Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 235000013856 polydextrose Nutrition 0.000 description 2
- 239000001259 polydextrose Substances 0.000 description 2
- 229940035035 polydextrose Drugs 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- GRWFGVWFFZKLTI-UHFFFAOYSA-N rac-alpha-Pinene Natural products CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 description 2
- 206010039722 scoliosis Diseases 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000017454 sodium diacetate Nutrition 0.000 description 2
- 239000001394 sodium malate Substances 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 235000019331 sodium stearoyl fumarate Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- KLIHEXMXHXUHHB-LTRPLHCISA-M sodium;(e)-4-octadecanoyloxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC(=O)\C=C\C([O-])=O KLIHEXMXHXUHHB-LTRPLHCISA-M 0.000 description 2
- 239000008279 sol Substances 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 229940035044 sorbitan monolaurate Drugs 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 2
- 239000001570 sorbitan monopalmitate Substances 0.000 description 2
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 2
- 235000011076 sorbitan monostearate Nutrition 0.000 description 2
- 239000001587 sorbitan monostearate Substances 0.000 description 2
- 229940035048 sorbitan monostearate Drugs 0.000 description 2
- 235000011078 sorbitan tristearate Nutrition 0.000 description 2
- 239000001589 sorbitan tristearate Substances 0.000 description 2
- 229960004129 sorbitan tristearate Drugs 0.000 description 2
- 208000002320 spinal muscular atrophy Diseases 0.000 description 2
- 235000013826 starch sodium octenyl succinate Nutrition 0.000 description 2
- 239000001334 starch sodium octenyl succinate Substances 0.000 description 2
- 229940114926 stearate Drugs 0.000 description 2
- 235000019330 stearyl citrate Nutrition 0.000 description 2
- 235000011075 stearyl tartrate Nutrition 0.000 description 2
- 239000001574 stearyl tartrate Substances 0.000 description 2
- RYGCHSSZXHQCEJ-UHFFFAOYSA-N stearyl tartrate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)C(O)C(O)C(=O)OCCCCCCCCCCCCCCCCCC RYGCHSSZXHQCEJ-UHFFFAOYSA-N 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 229940033134 talc Drugs 0.000 description 2
- 238000003419 tautomerization reaction Methods 0.000 description 2
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- 235000010215 titanium dioxide Nutrition 0.000 description 2
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 2
- 229960000984 tocofersolan Drugs 0.000 description 2
- 239000006208 topical dosage form Substances 0.000 description 2
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 229960002117 triamcinolone acetonide Drugs 0.000 description 2
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 2
- OGLDWXZKYODSOB-UHFFFAOYSA-N α-phellandrene Chemical compound CC(C)C1CC=C(C)C=C1 OGLDWXZKYODSOB-UHFFFAOYSA-N 0.000 description 2
- YHQGMYUVUMAZJR-UHFFFAOYSA-N α-terpinene Chemical compound CC(C)C1=CC=C(C)CC1 YHQGMYUVUMAZJR-UHFFFAOYSA-N 0.000 description 2
- 239000002076 α-tocopherol Substances 0.000 description 2
- 235000004835 α-tocopherol Nutrition 0.000 description 2
- OGCGGWYLHSJRFY-SECBINFHSA-N (+)-alpha-Campholenal Natural products CC1=CC[C@H](CC=O)C1(C)C OGCGGWYLHSJRFY-SECBINFHSA-N 0.000 description 1
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- 229930007066 (+)-dihydrocarvone Natural products 0.000 description 1
- AZOCECCLWFDTAP-RKDXNWHRSA-N (+)-dihydrocarvone Chemical compound C[C@@H]1CC[C@@H](C(C)=C)CC1=O AZOCECCLWFDTAP-RKDXNWHRSA-N 0.000 description 1
- NFLGAXVYCFJBMK-RKDXNWHRSA-N (+)-isomenthone Natural products CC(C)[C@H]1CC[C@@H](C)CC1=O NFLGAXVYCFJBMK-RKDXNWHRSA-N 0.000 description 1
- NZGWDASTMWDZIW-MRVPVSSYSA-N (+)-pulegone Chemical compound C[C@@H]1CCC(=C(C)C)C(=O)C1 NZGWDASTMWDZIW-MRVPVSSYSA-N 0.000 description 1
- WTARULDDTDQWMU-RKDXNWHRSA-N (+)-β-pinene Chemical compound C1[C@H]2C(C)(C)[C@@H]1CCC2=C WTARULDDTDQWMU-RKDXNWHRSA-N 0.000 description 1
- WTARULDDTDQWMU-IUCAKERBSA-N (-)-Nopinene Natural products C1[C@@H]2C(C)(C)[C@H]1CCC2=C WTARULDDTDQWMU-IUCAKERBSA-N 0.000 description 1
- RGZSQWQPBWRIAQ-CABCVRRESA-N (-)-alpha-Bisabolol Chemical compound CC(C)=CCC[C@](C)(O)[C@H]1CCC(C)=CC1 RGZSQWQPBWRIAQ-CABCVRRESA-N 0.000 description 1
- 229930006727 (-)-endo-fenchol Natural products 0.000 description 1
- CQUAYTJDLQBXCQ-NHYWBVRUSA-N (-)-isolongifolene Chemical compound C([C@@H](C1)C2(C)C)C[C@]31C2=CCCC3(C)C CQUAYTJDLQBXCQ-NHYWBVRUSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- BAVONGHXFVOKBV-ZJUUUORDSA-N (-)-trans-carveol Natural products CC(=C)[C@@H]1CC=C(C)[C@@H](O)C1 BAVONGHXFVOKBV-ZJUUUORDSA-N 0.000 description 1
- GDIYABNICDPBCR-UHFFFAOYSA-N (1-tert-butylcyclohexyl) acetate Chemical compound CC(=O)OC1(C(C)(C)C)CCCCC1 GDIYABNICDPBCR-UHFFFAOYSA-N 0.000 description 1
- PJOSHEDKRPRCAE-QHKWOANTSA-N (1e,6e)-4-(cyclobutylmethyl)-1,7-bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)C(C(=O)\C=C\C=1C=C(OC)C(OC)=CC=1)CC1CCC1 PJOSHEDKRPRCAE-QHKWOANTSA-N 0.000 description 1
- ZRHVOKYSOWTPIG-WCABBAIRSA-N (1r,3s,4s)-3-methoxy-4,7,7-trimethylbicyclo[2.2.1]heptane Chemical compound C1C[C@]2(C)[C@@H](OC)C[C@@H]1C2(C)C ZRHVOKYSOWTPIG-WCABBAIRSA-N 0.000 description 1
- XOKSLPVRUOBDEW-DJLDLDEBSA-N (1r,4s,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane Chemical compound C[C@H]1CC[C@H]2C(C)(C)[C@@H]1C2 XOKSLPVRUOBDEW-DJLDLDEBSA-N 0.000 description 1
- 239000001500 (2R)-6-methyl-2-[(1R)-4-methyl-1-cyclohex-3-enyl]hept-5-en-2-ol Substances 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- HLCSDJLATUNSSI-JXMROGBWSA-N (2e)-3,7-dimethylocta-2,6-dienenitrile Chemical compound CC(C)=CCC\C(C)=C\C#N HLCSDJLATUNSSI-JXMROGBWSA-N 0.000 description 1
- VLPIATFUUWWMKC-SNVBAGLBSA-N (2r)-1-(2,6-dimethylphenoxy)propan-2-amine Chemical compound C[C@@H](N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-SNVBAGLBSA-N 0.000 description 1
- LUEWUZLMQUOBSB-FSKGGBMCSA-N (2s,3s,4s,5s,6r)-2-[(2r,3s,4r,5r,6s)-6-[(2r,3s,4r,5s,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5s,6r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@@H](O[C@@H]2[C@H](O[C@@H](OC3[C@H](O[C@@H](O)[C@@H](O)[C@H]3O)CO)[C@@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-FSKGGBMCSA-N 0.000 description 1
- HCHFRAXBELVCGG-JYFOCSDGSA-N (2z,3z)-2,3-bis[(4-methoxyphenyl)methylidene]butanedinitrile Chemical compound C1=CC(OC)=CC=C1\C=C(/C#N)\C(\C#N)=C\C1=CC=C(OC)C=C1 HCHFRAXBELVCGG-JYFOCSDGSA-N 0.000 description 1
- 239000001490 (3R)-3,7-dimethylocta-1,6-dien-3-ol Substances 0.000 description 1
- DMASLKHVQRHNES-UPOGUZCLSA-N (3R)-beta,beta-caroten-3-ol Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C DMASLKHVQRHNES-UPOGUZCLSA-N 0.000 description 1
- ABTRFGSPYXCGMR-KXQOOQHDSA-N (3R)-beta,psi-caroten-3-ol Chemical compound CC(C)=CCCC(C)=CC=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C ABTRFGSPYXCGMR-KXQOOQHDSA-N 0.000 description 1
- JKQXZKUSFCKOGQ-JLGXGRJMSA-N (3R,3'R)-beta,beta-carotene-3,3'-diol Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-JLGXGRJMSA-N 0.000 description 1
- VYIRVAXUEZSDNC-TXDLOWMYSA-N (3R,3'S,5'R)-3,3'-dihydroxy-beta-kappa-caroten-6'-one Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC(=O)[C@]1(C)C[C@@H](O)CC1(C)C VYIRVAXUEZSDNC-TXDLOWMYSA-N 0.000 description 1
- GVOIABOMXKDDGU-XRODXAHISA-N (3S,3'S,5R,5'R)-3,3'-dihydroxy-kappa,kappa-carotene-6,6'-dione Chemical compound O=C([C@@]1(C)C(C[C@H](O)C1)(C)C)/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC(=O)[C@]1(C)C[C@@H](O)CC1(C)C GVOIABOMXKDDGU-XRODXAHISA-N 0.000 description 1
- GVOIABOMXKDDGU-LOFNIBRQSA-N (3S,3'S,5R,5'R)-3,3'-dihydroxy-kappa,kappa-carotene-6,6'-dione Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C(=O)C1(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC(=O)C2(C)CC(O)CC2(C)C GVOIABOMXKDDGU-LOFNIBRQSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- VIVCRCODGMFTFY-DVKNGEFBSA-N (3r,4s,5s)-3,4-dihydroxy-5-[(1r,2r)-1,2,3-trihydroxypropyl]oxolan-2-one Chemical compound OC[C@@H](O)[C@@H](O)[C@@H]1OC(=O)[C@H](O)[C@@H]1O VIVCRCODGMFTFY-DVKNGEFBSA-N 0.000 description 1
- NUFKRGBSZPCGQB-FLBSXDLDSA-N (3s)-3-amino-4-oxo-4-[[(2r)-1-oxo-1-[(2,2,4,4-tetramethylthietan-3-yl)amino]propan-2-yl]amino]butanoic acid;pentahydrate Chemical compound O.O.O.O.O.OC(=O)C[C@H](N)C(=O)N[C@H](C)C(=O)NC1C(C)(C)SC1(C)C.OC(=O)C[C@H](N)C(=O)N[C@H](C)C(=O)NC1C(C)(C)SC1(C)C NUFKRGBSZPCGQB-FLBSXDLDSA-N 0.000 description 1
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 description 1
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 1
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- CDOSHBSSFJOMGT-JTQLQIEISA-N (R)-linalool Natural products CC(C)=CCC[C@@](C)(O)C=C CDOSHBSSFJOMGT-JTQLQIEISA-N 0.000 description 1
- WUOACPNHFRMFPN-SECBINFHSA-N (S)-(-)-alpha-terpineol Chemical compound CC1=CC[C@@H](C(C)(C)O)CC1 WUOACPNHFRMFPN-SECBINFHSA-N 0.000 description 1
- 239000001733 1,4-Heptonolactone Substances 0.000 description 1
- 235000019298 1,4-Heptonolactone Nutrition 0.000 description 1
- VPKMGDRERYMTJX-CMDGGOBGSA-N 1-(2,6,6-Trimethyl-2-cyclohexen-1-yl)-1-penten-3-one Chemical compound CCC(=O)\C=C\C1C(C)=CCCC1(C)C VPKMGDRERYMTJX-CMDGGOBGSA-N 0.000 description 1
- KBHWKXNXTURZCD-UHFFFAOYSA-N 1-Methoxy-4-propylbenzene Chemical compound CCCC1=CC=C(OC)C=C1 KBHWKXNXTURZCD-UHFFFAOYSA-N 0.000 description 1
- WWFDJIVIDXJAQR-FFWSQMGZSA-N 1-[(2R,3R,4R,5R)-4-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[(2R,3R,4R,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-sulfanylphosphoryl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(2-amino-6-oxo-1H-purin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(6-aminopurin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(6-aminopurin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(6-aminopurin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(6-aminopurin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(hydroxymethyl)-3-(2-methoxyethoxy)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound COCCO[C@@H]1[C@H](O)[C@@H](COP(O)(=S)O[C@@H]2[C@@H](COP(S)(=O)O[C@@H]3[C@@H](COP(O)(=S)O[C@@H]4[C@@H](COP(O)(=S)O[C@@H]5[C@@H](COP(O)(=S)O[C@@H]6[C@@H](COP(O)(=S)O[C@@H]7[C@@H](COP(O)(=S)O[C@@H]8[C@@H](COP(O)(=S)O[C@@H]9[C@@H](COP(O)(=S)O[C@@H]%10[C@@H](COP(O)(=S)O[C@@H]%11[C@@H](COP(O)(=S)O[C@@H]%12[C@@H](COP(O)(=S)O[C@@H]%13[C@@H](COP(O)(=S)O[C@@H]%14[C@@H](COP(O)(=S)O[C@@H]%15[C@@H](COP(O)(=S)O[C@@H]%16[C@@H](COP(O)(=S)O[C@@H]%17[C@@H](COP(O)(=S)O[C@@H]%18[C@@H](CO)O[C@H]([C@@H]%18OCCOC)n%18cc(C)c(=O)[nH]c%18=O)O[C@H]([C@@H]%17OCCOC)n%17cc(C)c(N)nc%17=O)O[C@H]([C@@H]%16OCCOC)n%16cnc%17c(N)ncnc%16%17)O[C@H]([C@@H]%15OCCOC)n%15cc(C)c(N)nc%15=O)O[C@H]([C@@H]%14OCCOC)n%14cc(C)c(=O)[nH]c%14=O)O[C@H]([C@@H]%13OCCOC)n%13cc(C)c(=O)[nH]c%13=O)O[C@H]([C@@H]%12OCCOC)n%12cc(C)c(=O)[nH]c%12=O)O[C@H]([C@@H]%11OCCOC)n%11cc(C)c(N)nc%11=O)O[C@H]([C@@H]%10OCCOC)n%10cnc%11c(N)ncnc%10%11)O[C@H]([C@@H]9OCCOC)n9cc(C)c(=O)[nH]c9=O)O[C@H]([C@@H]8OCCOC)n8cnc9c(N)ncnc89)O[C@H]([C@@H]7OCCOC)n7cnc8c(N)ncnc78)O[C@H]([C@@H]6OCCOC)n6cc(C)c(=O)[nH]c6=O)O[C@H]([C@@H]5OCCOC)n5cnc6c5nc(N)[nH]c6=O)O[C@H]([C@@H]4OCCOC)n4cc(C)c(N)nc4=O)O[C@H]([C@@H]3OCCOC)n3cc(C)c(=O)[nH]c3=O)O[C@H]([C@@H]2OCCOC)n2cnc3c2nc(N)[nH]c3=O)O[C@H]1n1cnc2c1nc(N)[nH]c2=O WWFDJIVIDXJAQR-FFWSQMGZSA-N 0.000 description 1
- OZOMQRBLCMDCEG-CHHVJCJISA-N 1-[(z)-[5-(4-nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N/N1C(=O)NC(=O)C1 OZOMQRBLCMDCEG-CHHVJCJISA-N 0.000 description 1
- DBEDTBJGEXDPBT-UHFFFAOYSA-N 1-amino-4-hydroxy-3,3-bis(hydroxymethyl)butane-1-sulfonic acid Chemical compound OS(=O)(=O)C(N)CC(CO)(CO)CO DBEDTBJGEXDPBT-UHFFFAOYSA-N 0.000 description 1
- GKDLTXYXODKDEA-UHFFFAOYSA-N 1-phenylbutan-2-one Chemical compound CCC(=O)CC1=CC=CC=C1 GKDLTXYXODKDEA-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- GRWFGVWFFZKLTI-IUCAKERBSA-N 1S,5S-(-)-alpha-Pinene Natural products CC1=CC[C@@H]2C(C)(C)[C@H]1C2 GRWFGVWFFZKLTI-IUCAKERBSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-N 2,2-diethylpropanedioic acid Chemical compound CCC(CC)(C(O)=O)C(O)=O LTMRRSWNXVJMBA-UHFFFAOYSA-N 0.000 description 1
- RWYRUDPAALLKPX-UHFFFAOYSA-N 2,2-difluoro-n-methylethanamine;hydrochloride Chemical compound Cl.CNCC(F)F RWYRUDPAALLKPX-UHFFFAOYSA-N 0.000 description 1
- KVGYAHNHKCCHSP-UHFFFAOYSA-N 2,2-dimethyloctanal Chemical compound CCCCCCC(C)(C)C=O KVGYAHNHKCCHSP-UHFFFAOYSA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N 2,3,4,5-tetrahydroxypentanal Chemical compound OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- BEARMGATPGLSKG-UHFFFAOYSA-N 2,6-dimethyloct-7-en-2-yl acetate Chemical compound C=CC(C)CCCC(C)(C)OC(C)=O BEARMGATPGLSKG-UHFFFAOYSA-N 0.000 description 1
- WRFXXJKURVTLSY-UHFFFAOYSA-N 2,6-dimethyloctan-2-ol Chemical compound CCC(C)CCCC(C)(C)O WRFXXJKURVTLSY-UHFFFAOYSA-N 0.000 description 1
- FACFHHMQICTXFZ-UHFFFAOYSA-N 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)ethanamine Chemical compound N1=C2C=CC=CN2C(CCN)=C1C1=CC=CC=C1 FACFHHMQICTXFZ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 1
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- HVGZQCSMLUDISR-UHFFFAOYSA-N 2-Phenylethyl propanoate Chemical compound CCC(=O)OCCC1=CC=CC=C1 HVGZQCSMLUDISR-UHFFFAOYSA-N 0.000 description 1
- LIZVXGBYTGTTTI-UHFFFAOYSA-N 2-[(4-methylphenyl)sulfonylamino]-2-phenylacetic acid Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(C(O)=O)C1=CC=CC=C1 LIZVXGBYTGTTTI-UHFFFAOYSA-N 0.000 description 1
- XHRCFGDFESIFRG-UHFFFAOYSA-N 2-chloro-n-ethyl-n-[(2-methylphenyl)methyl]ethanamine Chemical compound ClCCN(CC)CC1=CC=CC=C1C XHRCFGDFESIFRG-UHFFFAOYSA-N 0.000 description 1
- KQMCGGGTJKNIMC-UHFFFAOYSA-N 2-hydroxy-3-propyl-2h-furan-5-one Chemical compound CCCC1=CC(=O)OC1O KQMCGGGTJKNIMC-UHFFFAOYSA-N 0.000 description 1
- KIHBGTRZFAVZRV-UHFFFAOYSA-N 2-hydroxyoctadecanoic acid Chemical class CCCCCCCCCCCCCCCCC(O)C(O)=O KIHBGTRZFAVZRV-UHFFFAOYSA-N 0.000 description 1
- GGEODQBPYAWTPG-UHFFFAOYSA-N 2-methylnonan-2-yl acetate Chemical compound CCCCCCCC(C)(C)OC(C)=O GGEODQBPYAWTPG-UHFFFAOYSA-N 0.000 description 1
- KVKKTLBBYFABAZ-UHFFFAOYSA-N 2-phenylethyl 2-methylbutanoate Chemical compound CCC(C)C(=O)OCCC1=CC=CC=C1 KVKKTLBBYFABAZ-UHFFFAOYSA-N 0.000 description 1
- UQPLZHUFLPDORW-UHFFFAOYSA-N 2-phenylphenol;sodium Chemical compound [Na].OC1=CC=CC=C1C1=CC=CC=C1 UQPLZHUFLPDORW-UHFFFAOYSA-N 0.000 description 1
- CKPOABDCSSXDCY-UHFFFAOYSA-N 2-propan-2-yltetradecanoic acid Chemical compound CCCCCCCCCCCCC(C(C)C)C(O)=O CKPOABDCSSXDCY-UHFFFAOYSA-N 0.000 description 1
- DLHQZZUEERVIGQ-UHFFFAOYSA-N 3,7-dimethyl-3-octanol Chemical compound CCC(C)(O)CCCC(C)C DLHQZZUEERVIGQ-UHFFFAOYSA-N 0.000 description 1
- JRTBBCBDKSRRCY-UHFFFAOYSA-N 3,7-dimethyloct-6-en-3-ol Chemical compound CCC(C)(O)CCC=C(C)C JRTBBCBDKSRRCY-UHFFFAOYSA-N 0.000 description 1
- MTDAKBBUYMYKAR-UHFFFAOYSA-N 3,7-dimethyloct-6-enenitrile Chemical compound N#CCC(C)CCC=C(C)C MTDAKBBUYMYKAR-UHFFFAOYSA-N 0.000 description 1
- FUDNBFMOXDUIIE-UHFFFAOYSA-N 3,7-dimethylocta-1,6-diene Chemical compound C=CC(C)CCC=C(C)C FUDNBFMOXDUIIE-UHFFFAOYSA-N 0.000 description 1
- PRNCMAKCNVRZFX-UHFFFAOYSA-N 3,7-dimethyloctan-1-ol Chemical compound CC(C)CCCC(C)CCO PRNCMAKCNVRZFX-UHFFFAOYSA-N 0.000 description 1
- RBKRCARRXLFUGJ-UHFFFAOYSA-N 3,7-dimethyloctan-3-yl acetate Chemical compound CC(=O)OC(C)(CC)CCCC(C)C RBKRCARRXLFUGJ-UHFFFAOYSA-N 0.000 description 1
- BRMWTNUJHUMWMS-UHFFFAOYSA-N 3-Methylhistidine Natural products CN1C=NC(CC(N)C(O)=O)=C1 BRMWTNUJHUMWMS-UHFFFAOYSA-N 0.000 description 1
- BWVZAZPLUTUBKD-HXLKAFCPSA-N 3-[(1r,4r)-2,2,3-trimethyl-5-bicyclo[2.2.1]heptanyl]cyclohexan-1-ol Chemical compound C([C@@]1(C[C@]2(C(C1(C)C)C)[H])[H])C2C1CCCC(O)C1 BWVZAZPLUTUBKD-HXLKAFCPSA-N 0.000 description 1
- YYWZKGZIIKPPJZ-UHFFFAOYSA-N 4,6,6-trimethylbicyclo[3.1.1]heptan-4-ol Chemical compound C1C2C(C)(C)C1CCC2(O)C YYWZKGZIIKPPJZ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- HSEYYGFJBLWFGD-UHFFFAOYSA-N 4-methylsulfanyl-2-[(2-methylsulfanylpyridine-3-carbonyl)amino]butanoic acid Chemical compound CSCCC(C(O)=O)NC(=O)C1=CC=CN=C1SC HSEYYGFJBLWFGD-UHFFFAOYSA-N 0.000 description 1
- DNKRHWDRVGJFDL-UHFFFAOYSA-N 4-pyridin-2-ylbenzoyl chloride Chemical compound C1=CC(C(=O)Cl)=CC=C1C1=CC=CC=N1 DNKRHWDRVGJFDL-UHFFFAOYSA-N 0.000 description 1
- FLDCSPABIQBYKP-UHFFFAOYSA-N 5-chloro-1,2-dimethylbenzimidazole Chemical compound ClC1=CC=C2N(C)C(C)=NC2=C1 FLDCSPABIQBYKP-UHFFFAOYSA-N 0.000 description 1
- WWJLCYHYLZZXBE-UHFFFAOYSA-N 5-chloro-1,3-dihydroindol-2-one Chemical compound ClC1=CC=C2NC(=O)CC2=C1 WWJLCYHYLZZXBE-UHFFFAOYSA-N 0.000 description 1
- 229940117976 5-hydroxylysine Drugs 0.000 description 1
- XXLFLUJXWKXUGS-UHFFFAOYSA-N 6-methoxyquinoline-4-carboxylic acid Chemical compound N1=CC=C(C(O)=O)C2=CC(OC)=CC=C21 XXLFLUJXWKXUGS-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ASKZRYGFUPSJPN-UHFFFAOYSA-N 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound CC1=CN2N=C(C=C(C)C2=N1)C1=CC(=O)N2C=C(C=CC2=N1)N1CCNC2(CC2)C1 ASKZRYGFUPSJPN-UHFFFAOYSA-N 0.000 description 1
- DFMMVLFMMAQXHZ-DOKBYWHISA-N 8'-apo-beta,psi-caroten-8'-al Chemical compound O=CC(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)/C=C/C1=C(C)CCCC1(C)C DFMMVLFMMAQXHZ-DOKBYWHISA-N 0.000 description 1
- QFIIYGZAUXVPSZ-UHFFFAOYSA-N 8-(2,4-dihydroxy-6-methylanilino)-2-(2,4-dihydroxy-6-methylphenyl)imino-7-hydroxy-1,9-dimethyldibenzofuran-3-one Chemical compound CC1=CC(=CC(=C1NC2=C(C3=C(C=C2O)OC4=CC(=O)C(=NC5=C(C=C(C=C5C)O)O)C(=C43)C)C)O)O QFIIYGZAUXVPSZ-UHFFFAOYSA-N 0.000 description 1
- ZOCUOMKMBMEYQV-GSLJADNHSA-N 9alpha-Fluoro-11beta,17alpha,21-trihydroxypregna-1,4-diene-3,20-dione 21-acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ZOCUOMKMBMEYQV-GSLJADNHSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 description 1
- 108010011376 AMP-Activated Protein Kinases Proteins 0.000 description 1
- 208000035657 Abasia Diseases 0.000 description 1
- 235000007173 Abies balsamea Nutrition 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- 229920000107 Acetylated distarch adipate Polymers 0.000 description 1
- 239000004356 Acetylated distarch glycerol Substances 0.000 description 1
- 241000722941 Achillea Species 0.000 description 1
- 244000205574 Acorus calamus Species 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 239000004377 Alitame Substances 0.000 description 1
- 239000004369 Alkaline modified starch Substances 0.000 description 1
- 239000004229 Alkannin Substances 0.000 description 1
- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 description 1
- CEZCCHQBSQPRMU-LLIZZRELSA-L Allura red AC Chemical compound [Na+].[Na+].COC1=CC(S([O-])(=O)=O)=C(C)C=C1\N=N\C1=C(O)C=CC2=CC(S([O-])(=O)=O)=CC=C12 CEZCCHQBSQPRMU-LLIZZRELSA-L 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 102100040743 Alpha-crystallin B chain Human genes 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 235000009328 Amaranthus caudatus Nutrition 0.000 description 1
- 240000001592 Amaranthus caudatus Species 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 239000001741 Ammonium adipate Substances 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 239000001729 Ammonium fumarate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000004251 Ammonium lactate Substances 0.000 description 1
- 239000001715 Ammonium malate Substances 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 244000099147 Ananas comosus Species 0.000 description 1
- 235000007119 Ananas comosus Nutrition 0.000 description 1
- 235000011514 Anogeissus latifolia Nutrition 0.000 description 1
- 244000106483 Anogeissus latifolia Species 0.000 description 1
- 206010003084 Areflexia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- JEBFVOLFMLUKLF-IFPLVEIFSA-N Astaxanthin Natural products CC(=C/C=C/C(=C/C=C/C1=C(C)C(=O)C(O)CC1(C)C)/C)C=CC=C(/C)C=CC=C(/C)C=CC2=C(C)C(=O)C(O)CC2(C)C JEBFVOLFMLUKLF-IFPLVEIFSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- 101710089791 BAG family molecular chaperone regulator 3 Proteins 0.000 description 1
- 239000007989 BIS-Tris Propane buffer Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000004857 Balsam Substances 0.000 description 1
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 1
- 235000021357 Behenic acid Nutrition 0.000 description 1
- HRQKOYFGHJYEFS-UHFFFAOYSA-N Beta psi-carotene Chemical compound CC(C)=CCCC(C)=CC=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C HRQKOYFGHJYEFS-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- DHHFDKNIEVKVKS-FMOSSLLZSA-N Betanin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC(C(=C1)O)=CC(C[C@H]2C([O-])=O)=C1[N+]2=C\C=C\1C=C(C(O)=O)N[C@H](C(O)=O)C/1 DHHFDKNIEVKVKS-FMOSSLLZSA-N 0.000 description 1
- DHHFDKNIEVKVKS-MVUYWVKGSA-N Betanin Natural products O=C(O)[C@@H]1NC(C(=O)O)=C/C(=C\C=[N+]/2\[C@@H](C(=O)[O-])Cc3c\2cc(O)c(O[C@H]2[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O2)c3)/C1 DHHFDKNIEVKVKS-MVUYWVKGSA-N 0.000 description 1
- 208000006304 Bethlem myopathy Diseases 0.000 description 1
- 235000018185 Betula X alpestris Nutrition 0.000 description 1
- 235000018212 Betula X uliginosa Nutrition 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 244000017106 Bixa orellana Species 0.000 description 1
- RAFGELQLHMBRHD-VFYVRILKSA-N Bixin Natural products COC(=O)C=CC(=C/C=C/C(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C(=O)O)/C)C RAFGELQLHMBRHD-VFYVRILKSA-N 0.000 description 1
- 239000004370 Bleached starch Substances 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 239000004135 Bone phosphate Substances 0.000 description 1
- 235000007689 Borago officinalis Nutrition 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 description 1
- 108010004032 Bromelains Proteins 0.000 description 1
- 239000001842 Brominated vegetable oil Substances 0.000 description 1
- 235000004936 Bromus mango Nutrition 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- RTMBGDBBDQKNNZ-UHFFFAOYSA-L C.I. Acid Blue 3 Chemical compound [Ca+2].C1=CC(N(CC)CC)=CC=C1C(C=1C(=CC(=C(O)C=1)S([O-])(=O)=O)S([O-])(=O)=O)=C1C=CC(=[N+](CC)CC)C=C1.C1=CC(N(CC)CC)=CC=C1C(C=1C(=CC(=C(O)C=1)S([O-])(=O)=O)S([O-])(=O)=O)=C1C=CC(=[N+](CC)CC)C=C1 RTMBGDBBDQKNNZ-UHFFFAOYSA-L 0.000 description 1
- 102100033849 CCHC-type zinc finger nucleic acid binding protein Human genes 0.000 description 1
- 108091033409 CRISPR Proteins 0.000 description 1
- 238000010453 CRISPR/Cas method Methods 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 235000011996 Calamus deerratus Nutrition 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- CBOCVOKPQGJKKJ-UHFFFAOYSA-L Calcium formate Chemical compound [Ca+2].[O-]C=O.[O-]C=O CBOCVOKPQGJKKJ-UHFFFAOYSA-L 0.000 description 1
- 239000001749 Calcium fumarate Substances 0.000 description 1
- 239000001736 Calcium glycerylphosphate Substances 0.000 description 1
- 239000004132 Calcium polyphosphate Substances 0.000 description 1
- BCZXFFBUYPCTSJ-UHFFFAOYSA-L Calcium propionate Chemical compound [Ca+2].CCC([O-])=O.CCC([O-])=O BCZXFFBUYPCTSJ-UHFFFAOYSA-L 0.000 description 1
- 239000004136 Calcium sodium polyphosphate Substances 0.000 description 1
- 241001631457 Cannula Species 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- VYIRVAXUEZSDNC-LOFNIBRQSA-N Capsanthyn Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC(=O)C2(C)CC(O)CC2(C)C VYIRVAXUEZSDNC-LOFNIBRQSA-N 0.000 description 1
- 235000002566 Capsicum Nutrition 0.000 description 1
- GVOIABOMXKDDGU-SUKXYCKUSA-N Capsorubin Natural products O=C(/C=C/C(=C\C=C\C(=C/C=C/C=C(\C=C\C=C(/C=C/C(=O)[C@@]1(C)C(C)(C)C[C@H](O)C1)\C)/C)\C)/C)[C@@]1(C)C(C)(C)C[C@H](O)C1 GVOIABOMXKDDGU-SUKXYCKUSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- YSVBPNGJESBVRM-ZPZFBZIMSA-L Carmoisine Chemical compound [Na+].[Na+].C1=CC=C2C(/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)O)=CC=C(S([O-])(=O)=O)C2=C1 YSVBPNGJESBVRM-ZPZFBZIMSA-L 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- 235000009024 Ceanothus sanguineus Nutrition 0.000 description 1
- 241000218645 Cedrus Species 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- NPBVQXIMTZKSBA-UHFFFAOYSA-N Chavibetol Natural products COC1=CC=C(CC=C)C=C1O NPBVQXIMTZKSBA-UHFFFAOYSA-N 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004155 Chlorine dioxide Substances 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 239000004381 Choline salt Substances 0.000 description 1
- IFYMEZNJCAQUME-APKWKYNESA-N Chrysanthemaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C1OC2(C)CC(O)CC(C)(C)C2=C1)C=CC=C(/C)C=CC3=C(C)CC(O)CC3(C)C IFYMEZNJCAQUME-APKWKYNESA-N 0.000 description 1
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 1
- 244000037364 Cinnamomum aromaticum Species 0.000 description 1
- 235000014489 Cinnamomum aromaticum Nutrition 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- 244000223760 Cinnamomum zeylanicum Species 0.000 description 1
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 description 1
- 239000004217 Citranaxanthin Substances 0.000 description 1
- SLQHGWZKKZPZEK-JKEZLOPUSA-N Citranaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C(=O)C)C=CC=C(/C)C=CC1=C(C)CCCC1(C)C SLQHGWZKKZPZEK-JKEZLOPUSA-N 0.000 description 1
- 239000001793 Citric acid esters of mono and diglycerides of fatty acids Substances 0.000 description 1
- JOZKFWLRHCDGJA-LLVKDONJSA-N Citronellyl acetate Natural products CC(=O)OCC[C@H](C)CCC=C(C)C JOZKFWLRHCDGJA-LLVKDONJSA-N 0.000 description 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- 244000183685 Citrus aurantium Species 0.000 description 1
- 235000007716 Citrus aurantium Nutrition 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 241000555678 Citrus unshiu Species 0.000 description 1
- FBRAWBYQGRLCEK-AVVSTMBFSA-N Clobetasone butyrate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CCC)[C@@]1(C)CC2=O FBRAWBYQGRLCEK-AVVSTMBFSA-N 0.000 description 1
- 101150117670 Cnbp gene Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 235000002787 Coriandrum sativum Nutrition 0.000 description 1
- 244000018436 Coriandrum sativum Species 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- 244000107602 Corymbia citriodora Species 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- 235000015655 Crocus sativus Nutrition 0.000 description 1
- 244000124209 Crocus sativus Species 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 239000004212 Cryptoxanthin Substances 0.000 description 1
- 244000241257 Cucumis melo Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- 241000218691 Cupressaceae Species 0.000 description 1
- 235000003392 Curcuma domestica Nutrition 0.000 description 1
- 244000008991 Curcuma longa Species 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- 206010011655 Cushingoid Diseases 0.000 description 1
- 244000007835 Cyamopsis tetragonoloba Species 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- 229920000089 Cyclic olefin copolymer Polymers 0.000 description 1
- 240000004784 Cymbopogon citratus Species 0.000 description 1
- 235000017897 Cymbopogon citratus Nutrition 0.000 description 1
- 244000166652 Cymbopogon martinii Species 0.000 description 1
- 244000166675 Cymbopogon nardus Species 0.000 description 1
- 235000018791 Cymbopogon nardus Nutrition 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- HSMMSDWNEJLVRY-UHFFFAOYSA-N DDAIP Chemical compound CCCCCCCCCCCCOC(=O)C(C)N(C)C HSMMSDWNEJLVRY-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 102100038694 DNA-binding protein SMUBP-2 Human genes 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 235000009355 Dianthus caryophyllus Nutrition 0.000 description 1
- 240000006497 Dianthus caryophyllus Species 0.000 description 1
- 239000004134 Dicalcium diphosphate Substances 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 1
- 239000001836 Dioctyl sodium sulphosuccinate Substances 0.000 description 1
- 235000008597 Diospyros kaki Nutrition 0.000 description 1
- 244000236655 Diospyros kaki Species 0.000 description 1
- 241000668724 Dipterocarpus turbinatus Species 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 239000004371 Distarch glycerol Substances 0.000 description 1
- 101710173648 DnaJ homolog subfamily B member 6 Proteins 0.000 description 1
- 102000004168 Dysferlin Human genes 0.000 description 1
- 108090000620 Dysferlin Proteins 0.000 description 1
- 208000037150 Dysferlin-related limb-girdle muscular dystrophy R2 Diseases 0.000 description 1
- 244000133098 Echinacea angustifolia Species 0.000 description 1
- 240000002943 Elettaria cardamomum Species 0.000 description 1
- 102100034239 Emerin Human genes 0.000 description 1
- HCHFRAXBELVCGG-UHFFFAOYSA-N Emerin Natural products C1=CC(OC)=CC=C1C=C(C#N)C(C#N)=CC1=CC=C(OC)C=C1 HCHFRAXBELVCGG-UHFFFAOYSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 229920000896 Ethulose Polymers 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 description 1
- 235000004722 Eucalyptus citriodora Nutrition 0.000 description 1
- 235000004692 Eucalyptus globulus Nutrition 0.000 description 1
- 239000005770 Eugenol Substances 0.000 description 1
- 241001539473 Euphoria Species 0.000 description 1
- 206010015535 Euphoric mood Diseases 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 206010051267 Facial paresis Diseases 0.000 description 1
- 208000001308 Fasciculation Diseases 0.000 description 1
- 239000004214 Fast Green FCF Substances 0.000 description 1
- RZSYLLSAWYUBPE-UHFFFAOYSA-L Fast green FCF Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC(O)=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 RZSYLLSAWYUBPE-UHFFFAOYSA-L 0.000 description 1
- 239000004277 Ferrous carbonate Substances 0.000 description 1
- DKKCQDROTDCQOR-UHFFFAOYSA-L Ferrous lactate Chemical compound [Fe+2].CC(O)C([O-])=O.CC(O)C([O-])=O DKKCQDROTDCQOR-UHFFFAOYSA-L 0.000 description 1
- 108090000270 Ficain Proteins 0.000 description 1
- 102000013366 Filamin Human genes 0.000 description 1
- 108060002900 Filamin Proteins 0.000 description 1
- 239000004211 Flavoxanthin Substances 0.000 description 1
- JRHJXXLCNATYLS-NGZWBNMCSA-N Flavoxanthin Chemical compound C/C([C@H]1C=C2C(C)(C)C[C@H](O)C[C@@]2(C)O1)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C JRHJXXLCNATYLS-NGZWBNMCSA-N 0.000 description 1
- QHUMOJKEVAPSCY-JOJDNVQPSA-N Flavoxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C1(C)OC2(C)CC(O)CC(C)(C)C2=C1)C=CC=C(/C)C=CC3C(=CC(O)CC3(C)C)C QHUMOJKEVAPSCY-JOJDNVQPSA-N 0.000 description 1
- UUOUOERPONYGOS-CLCRDYEYSA-N Fluocinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3C[C@H](F)C2=C1 UUOUOERPONYGOS-CLCRDYEYSA-N 0.000 description 1
- WJOHZNCJWYWUJD-IUGZLZTKSA-N Fluocinonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WJOHZNCJWYWUJD-IUGZLZTKSA-N 0.000 description 1
- WHZRCUIISKRTJL-YTZKRAOUSA-N Fluocortolone caproate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)COC(=O)CCCCC)[C@@]2(C)C[C@@H]1O WHZRCUIISKRTJL-YTZKRAOUSA-N 0.000 description 1
- 240000006927 Foeniculum vulgare Species 0.000 description 1
- 235000004204 Foeniculum vulgare Nutrition 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 235000007297 Gaultheria procumbens Nutrition 0.000 description 1
- 240000001238 Gaultheria procumbens Species 0.000 description 1
- 229920002148 Gellan gum Polymers 0.000 description 1
- 239000005792 Geraniol Substances 0.000 description 1
- GLZPCOQZEFWAFX-YFHOEESVSA-N Geraniol Natural products CC(C)=CCC\C(C)=C/CO GLZPCOQZEFWAFX-YFHOEESVSA-N 0.000 description 1
- 241000208152 Geranium Species 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 229920002581 Glucomannan Polymers 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 108010008488 Glycylglycine Proteins 0.000 description 1
- 239000004378 Glycyrrhizin Substances 0.000 description 1
- 244000299507 Gossypium hirsutum Species 0.000 description 1
- 240000004282 Grewia occidentalis Species 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 239000001922 Gum ghatti Substances 0.000 description 1
- 229920000569 Gum karaya Polymers 0.000 description 1
- OWXMKDGYPWMGEB-UHFFFAOYSA-N HEPPS Chemical compound OCCN1CCN(CCCS(O)(=O)=O)CC1 OWXMKDGYPWMGEB-UHFFFAOYSA-N 0.000 description 1
- MUQNGPZZQDCDFT-JNQJZLCISA-N Halcinonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]1(C)C[C@@H]2O MUQNGPZZQDCDFT-JNQJZLCISA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 240000008669 Hedera helix Species 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- ZTJORNVITHUQJA-UHFFFAOYSA-N Heptyl p-hydroxybenzoate Chemical compound CCCCCCCOC(=O)C1=CC=C(O)C=C1 ZTJORNVITHUQJA-UHFFFAOYSA-N 0.000 description 1
- 239000004284 Heptyl p-hydroxybenzoate Substances 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000891982 Homo sapiens Alpha-crystallin B chain Proteins 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000697871 Homo sapiens BAG family molecular chaperone regulator 3 Proteins 0.000 description 1
- 101000665135 Homo sapiens DNA-binding protein SMUBP-2 Proteins 0.000 description 1
- 101000804112 Homo sapiens DnaJ homolog subfamily B member 6 Proteins 0.000 description 1
- 101001016184 Homo sapiens Dysferlin Proteins 0.000 description 1
- 101000972491 Homo sapiens Laminin subunit alpha-2 Proteins 0.000 description 1
- 101000588302 Homo sapiens Nuclear factor erythroid 2-related factor 2 Proteins 0.000 description 1
- 101001123963 Homo sapiens Protein O-mannosyl-transferase 1 Proteins 0.000 description 1
- 101001094684 Homo sapiens Protein O-mannosyl-transferase 2 Proteins 0.000 description 1
- 101000846198 Homo sapiens Ribitol 5-phosphate transferase FKRP Proteins 0.000 description 1
- 101000617738 Homo sapiens Survival motor neuron protein Proteins 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 101710091977 Hydrophobin Proteins 0.000 description 1
- 239000004362 Hydroxy propyl distarch glycerol Substances 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 229920003012 Hydroxypropyl distarch phosphate Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 235000008227 Illicium verum Nutrition 0.000 description 1
- 240000007232 Illicium verum Species 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 244000018716 Impatiens biflora Species 0.000 description 1
- 208000015580 Increased body weight Diseases 0.000 description 1
- 239000004233 Indanthrene blue RS Substances 0.000 description 1
- 208000032754 Infant Death Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 201000006347 Intellectual Disability Diseases 0.000 description 1
- 235000015164 Iris germanica var. florentina Nutrition 0.000 description 1
- KGEKLUUHTZCSIP-UHFFFAOYSA-N Isobornyl acetate Natural products C1CC2(C)C(OC(=O)C)CC1C2(C)C KGEKLUUHTZCSIP-UHFFFAOYSA-N 0.000 description 1
- BJIOGJUNALELMI-ONEGZZNKSA-N Isoeugenol Natural products COC1=CC(\C=C\C)=CC=C1O BJIOGJUNALELMI-ONEGZZNKSA-N 0.000 description 1
- 239000002310 Isopropyl citrate Substances 0.000 description 1
- 235000010254 Jasminum officinale Nutrition 0.000 description 1
- 240000005385 Jasminum sambac Species 0.000 description 1
- 241000721662 Juniperus Species 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 108010084772 LIM Domain Proteins Proteins 0.000 description 1
- 102000005633 LIM Domain Proteins Human genes 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000001834 Lactylated fatty acid esters of glycerol and propane-1 Substances 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 244000165082 Lavanda vera Species 0.000 description 1
- 235000010663 Lavandula angustifolia Nutrition 0.000 description 1
- 235000010658 Lavandula latifolia Nutrition 0.000 description 1
- 244000178860 Lavandula latifolia Species 0.000 description 1
- 240000003553 Leptospermum scoparium Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 235000004431 Linum usitatissimum Nutrition 0.000 description 1
- 240000006240 Linum usitatissimum Species 0.000 description 1
- 206010062315 Lipohypertrophy Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 235000012854 Litsea cubeba Nutrition 0.000 description 1
- 240000002262 Litsea cubeba Species 0.000 description 1
- PDSNLYSELAIEBU-UHFFFAOYSA-N Longifolene Chemical compound C1CCC(C)(C)C2C3CCC2C1(C)C3=C PDSNLYSELAIEBU-UHFFFAOYSA-N 0.000 description 1
- ZPUKHRHPJKNORC-UHFFFAOYSA-N Longifolene Natural products CC1(C)CCCC2(C)C3CCC1(C3)C2=C ZPUKHRHPJKNORC-UHFFFAOYSA-N 0.000 description 1
- 235000015459 Lycium barbarum Nutrition 0.000 description 1
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 1
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 1
- JEVVKJMRZMXFBT-XWDZUXABSA-N Lycophyll Natural products OC/C(=C/CC/C(=C\C=C\C(=C/C=C/C(=C\C=C\C=C(/C=C/C=C(\C=C\C=C(/CC/C=C(/CO)\C)\C)/C)\C)/C)\C)/C)/C JEVVKJMRZMXFBT-XWDZUXABSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 235000014826 Mangifera indica Nutrition 0.000 description 1
- 240000007228 Mangifera indica Species 0.000 description 1
- WSTYNZDAOAEEKG-UHFFFAOYSA-N Mayol Natural products CC1=C(O)C(=O)C=C2C(CCC3(C4CC(C(CC4(CCC33C)C)=O)C)C)(C)C3=CC=C21 WSTYNZDAOAEEKG-UHFFFAOYSA-N 0.000 description 1
- 240000000233 Melia azedarach Species 0.000 description 1
- 235000010654 Melissa officinalis Nutrition 0.000 description 1
- 244000062730 Melissa officinalis Species 0.000 description 1
- 235000014435 Mentha Nutrition 0.000 description 1
- 241001072983 Mentha Species 0.000 description 1
- 235000014749 Mentha crispa Nutrition 0.000 description 1
- 244000078639 Mentha spicata Species 0.000 description 1
- NFLGAXVYCFJBMK-UHFFFAOYSA-N Menthone Chemical compound CC(C)C1CCC(C)CC1=O NFLGAXVYCFJBMK-UHFFFAOYSA-N 0.000 description 1
- 239000004145 Methyl glucoside-coconut oil ester Substances 0.000 description 1
- ICBJCVRQDSQPGI-UHFFFAOYSA-N Methyl hexyl ether Chemical compound CCCCCCOC ICBJCVRQDSQPGI-UHFFFAOYSA-N 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 201000001087 Miyoshi muscular dystrophy Diseases 0.000 description 1
- 208000009376 Miyoshi myopathy Diseases 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 244000179970 Monarda didyma Species 0.000 description 1
- 235000010672 Monarda didyma Nutrition 0.000 description 1
- 206010027951 Mood swings Diseases 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000002038 Muscle Hypertonia Diseases 0.000 description 1
- 102000008934 Muscle Proteins Human genes 0.000 description 1
- 108010074084 Muscle Proteins Proteins 0.000 description 1
- 206010028293 Muscle contractions involuntary Diseases 0.000 description 1
- 206010028347 Muscle twitching Diseases 0.000 description 1
- SUAUILGSCPYJCS-UHFFFAOYSA-N Musk ambrette Chemical compound COC1=C([N+]([O-])=O)C(C)=C([N+]([O-])=O)C=C1C(C)(C)C SUAUILGSCPYJCS-UHFFFAOYSA-N 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 235000009421 Myristica fragrans Nutrition 0.000 description 1
- 244000270834 Myristica fragrans Species 0.000 description 1
- 235000007265 Myrrhis odorata Nutrition 0.000 description 1
- JDHILDINMRGULE-LURJTMIESA-N N(pros)-methyl-L-histidine Chemical compound CN1C=NC=C1C[C@H](N)C(O)=O JDHILDINMRGULE-LURJTMIESA-N 0.000 description 1
- MXNRLFUSFKVQSK-UHFFFAOYSA-O N,N,N-Trimethyllysine Chemical compound C[N+](C)(C)CCCCC(N)C(O)=O MXNRLFUSFKVQSK-UHFFFAOYSA-O 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- YNLCVAQJIKOXER-UHFFFAOYSA-N N-[tris(hydroxymethyl)methyl]-3-aminopropanesulfonic acid Chemical compound OCC(CO)(CO)NCCCS(O)(=O)=O YNLCVAQJIKOXER-UHFFFAOYSA-N 0.000 description 1
- 108010029147 N-acylmannosamine kinase Proteins 0.000 description 1
- 229910000503 Na-aluminosilicate Inorganic materials 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004384 Neotame Substances 0.000 description 1
- GLZPCOQZEFWAFX-JXMROGBWSA-N Nerol Natural products CC(C)=CCC\C(C)=C\CO GLZPCOQZEFWAFX-JXMROGBWSA-N 0.000 description 1
- NVNLLIYOARQCIX-MSHCCFNRSA-N Nisin Chemical compound N1C(=O)[C@@H](CC(C)C)NC(=O)C(=C)NC(=O)[C@@H]([C@H](C)CC)NC(=O)[C@@H](NC(=O)C(=C/C)/NC(=O)[C@H](N)[C@H](C)CC)CSC[C@@H]1C(=O)N[C@@H]1C(=O)N2CCC[C@@H]2C(=O)NCC(=O)N[C@@H](C(=O)N[C@H](CCCCN)C(=O)N[C@@H]2C(NCC(=O)N[C@H](C)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCSC)C(=O)NCC(=O)N[C@H](CS[C@@H]2C)C(=O)N[C@H](CC(N)=O)C(=O)N[C@H](CCSC)C(=O)N[C@H](CCCCN)C(=O)N[C@@H]2C(N[C@H](C)C(=O)N[C@@H]3C(=O)N[C@@H](C(N[C@H](CC=4NC=NC=4)C(=O)N[C@H](CS[C@@H]3C)C(=O)N[C@H](CO)C(=O)N[C@H]([C@H](C)CC)C(=O)N[C@H](CC=3NC=NC=3)C(=O)N[C@H](C(C)C)C(=O)NC(=C)C(=O)N[C@H](CCCCN)C(O)=O)=O)CS[C@@H]2C)=O)=O)CS[C@@H]1C NVNLLIYOARQCIX-MSHCCFNRSA-N 0.000 description 1
- 108010053775 Nisin Proteins 0.000 description 1
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- ZVKOASAVGLETCT-UOGKPENDSA-N Norbixin Chemical compound OC(=O)/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)/C=C/C(O)=O ZVKOASAVGLETCT-UOGKPENDSA-N 0.000 description 1
- JERYLJRGLVHIEW-UENHKZIGSA-N Norbixin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C(=O)O)C=CC=CC=CC(=O)O JERYLJRGLVHIEW-UENHKZIGSA-N 0.000 description 1
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 235000010676 Ocimum basilicum Nutrition 0.000 description 1
- 240000007926 Ocimum gratissimum Species 0.000 description 1
- 244000227633 Ocotea pretiosa Species 0.000 description 1
- 235000004263 Ocotea pretiosa Nutrition 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000219925 Oenothera Species 0.000 description 1
- 235000004496 Oenothera biennis Nutrition 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 239000004235 Orange GGN Substances 0.000 description 1
- 239000004218 Orcein Substances 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 239000003216 Oxystearin Substances 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 208000007542 Paresis Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000006002 Pepper Substances 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 206010034719 Personality change Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- OOUTWVMJGMVRQF-DOYZGLONSA-N Phoenicoxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)C(=O)C(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)C(=O)CCC2(C)C OOUTWVMJGMVRQF-DOYZGLONSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 235000016761 Piper aduncum Nutrition 0.000 description 1
- 235000017804 Piper guineense Nutrition 0.000 description 1
- BHUIUXNAPJIDOG-UHFFFAOYSA-N Piperonol Chemical compound OCC1=CC=C2OCOC2=C1 BHUIUXNAPJIDOG-UHFFFAOYSA-N 0.000 description 1
- PFWYHTORQZAGCA-UHFFFAOYSA-N Piperonyl acetate Chemical compound CC(=O)OCC1=CC=C2OCOC2=C1 PFWYHTORQZAGCA-UHFFFAOYSA-N 0.000 description 1
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 description 1
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010035669 Pneumonia aspiration Diseases 0.000 description 1
- 235000011751 Pogostemon cablin Nutrition 0.000 description 1
- 240000002505 Pogostemon cablin Species 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004237 Ponceau 6R Substances 0.000 description 1
- 239000001747 Potassium fumarate Substances 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 102100028120 Protein O-mannosyl-transferase 1 Human genes 0.000 description 1
- 102100035490 Protein O-mannosyl-transferase 2 Human genes 0.000 description 1
- 208000032225 Proximal spinal muscular atrophy type 1 Diseases 0.000 description 1
- 208000033526 Proximal spinal muscular atrophy type 3 Diseases 0.000 description 1
- UVMRYBDEERADNV-UHFFFAOYSA-N Pseudoeugenol Natural products COC1=CC(C(C)=C)=CC=C1O UVMRYBDEERADNV-UHFFFAOYSA-N 0.000 description 1
- WTARULDDTDQWMU-UHFFFAOYSA-N Pseudopinene Natural products C1C2C(C)(C)C1CCC2=C WTARULDDTDQWMU-UHFFFAOYSA-N 0.000 description 1
- 241000508269 Psidium Species 0.000 description 1
- 206010037249 Psychotic behaviour Diseases 0.000 description 1
- 235000009984 Pterocarpus indicus Nutrition 0.000 description 1
- 244000086363 Pterocarpus indicus Species 0.000 description 1
- 244000294611 Punica granatum Species 0.000 description 1
- 235000014360 Punica granatum Nutrition 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- 206010039020 Rhabdomyolysis Diseases 0.000 description 1
- 239000004216 Rhodoxanthin Substances 0.000 description 1
- VWXMLZQUDPCJPL-ZDHAIZATSA-N Rhodoxanthin Chemical compound CC\1=CC(=O)CC(C)(C)C/1=C\C=C(/C)\C=C\C=C(/C)\C=C\C=C\C(\C)=C\C=C\C(\C)=C\C=C1\C(C)=CC(=O)CC1(C)C VWXMLZQUDPCJPL-ZDHAIZATSA-N 0.000 description 1
- VWXMLZQUDPCJPL-XPZLFLLQSA-N Rhodoxanthin Natural products O=C1C=C(C)/C(=C\C=C(/C=C/C=C(\C=C\C=C\C(=C/C=C/C(=C\C=C\2/C(C)=CC(=O)CC/2(C)C)/C)\C)/C)\C)/C(C)(C)C1 VWXMLZQUDPCJPL-XPZLFLLQSA-N 0.000 description 1
- 235000001537 Ribes X gardonianum Nutrition 0.000 description 1
- 235000001535 Ribes X utile Nutrition 0.000 description 1
- 235000016919 Ribes petraeum Nutrition 0.000 description 1
- 244000281247 Ribes rubrum Species 0.000 description 1
- 235000002355 Ribes spicatum Nutrition 0.000 description 1
- 102100031774 Ribitol 5-phosphate transferase FKRP Human genes 0.000 description 1
- 101710087566 Ribitol-5-phosphate transferase FKTN Proteins 0.000 description 1
- 239000004228 Riboflavin-5'-Phosphate Substances 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 244000178231 Rosmarinus officinalis Species 0.000 description 1
- 235000017304 Ruaghas Nutrition 0.000 description 1
- 101150081851 SMN1 gene Proteins 0.000 description 1
- 101150015954 SMN2 gene Proteins 0.000 description 1
- 235000002911 Salvia sclarea Nutrition 0.000 description 1
- 244000182022 Salvia sclarea Species 0.000 description 1
- 240000000513 Santalum album Species 0.000 description 1
- 235000008632 Santalum album Nutrition 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 102100023781 Selenoprotein N Human genes 0.000 description 1
- 101710095024 Selenoprotein N Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 244000040738 Sesamum orientale Species 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 239000004115 Sodium Silicate Substances 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000004288 Sodium dehydroacetate Substances 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- 239000001744 Sodium fumarate Substances 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 239000004283 Sodium sorbate Substances 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 229920001304 Solutol HS 15 Polymers 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000033145 Spinal muscular atrophy with respiratory distress type 1 Diseases 0.000 description 1
- 235000009184 Spondias indica Nutrition 0.000 description 1
- 239000004355 Starch acetate esterified with vinyl acetate Substances 0.000 description 1
- 241000934878 Sterculia Species 0.000 description 1
- 239000004383 Steviol glycoside Substances 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000001833 Succinylated monoglyceride Substances 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- OIQPTROHQCGFEF-QIKYXUGXSA-L Sunset Yellow FCF Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-QIKYXUGXSA-L 0.000 description 1
- 102100021947 Survival motor neuron protein Human genes 0.000 description 1
- 241000779819 Syncarpia glomulifera Species 0.000 description 1
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 1
- 235000013584 Tabebuia pallida Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 241001441724 Tetraodontidae Species 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 235000008109 Thuja occidentalis Nutrition 0.000 description 1
- 241000736892 Thujopsis dolabrata Species 0.000 description 1
- 239000005844 Thymol Substances 0.000 description 1
- 235000007303 Thymus vulgaris Nutrition 0.000 description 1
- 240000002657 Thymus vulgaris Species 0.000 description 1
- 240000006909 Tilia x europaea Species 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- 206010068872 Toe walking Diseases 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 239000007997 Tricine buffer Substances 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 229920001777 Tupperware Polymers 0.000 description 1
- 208000034953 Twin anemia-polycythemia sequence Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 240000000851 Vaccinium corymbosum Species 0.000 description 1
- 235000003095 Vaccinium corymbosum Nutrition 0.000 description 1
- 240000001717 Vaccinium macrocarpon Species 0.000 description 1
- 235000012545 Vaccinium macrocarpon Nutrition 0.000 description 1
- 235000017537 Vaccinium myrtillus Nutrition 0.000 description 1
- 235000002118 Vaccinium oxycoccus Nutrition 0.000 description 1
- 235000013832 Valeriana officinalis Nutrition 0.000 description 1
- 244000126014 Valeriana officinalis Species 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 235000007769 Vetiveria zizanioides Nutrition 0.000 description 1
- 244000284012 Vetiveria zizanioides Species 0.000 description 1
- 239000004213 Violaxanthin Substances 0.000 description 1
- SZCBXWMUOPQSOX-LOFNIBRQSA-N Violaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C12OC1(C)CC(O)CC2(C)C)C=CC=C(/C)C=CC34OC3(C)CC(O)CC4(C)C SZCBXWMUOPQSOX-LOFNIBRQSA-N 0.000 description 1
- 208000021017 Weight Gain Diseases 0.000 description 1
- 208000026481 Werdnig-Hoffmann disease Diseases 0.000 description 1
- 210000001766 X chromosome Anatomy 0.000 description 1
- 208000015953 X-linked Emery-Dreifuss muscular dystrophy Diseases 0.000 description 1
- 201000001520 X-linked Emery-Dreifuss muscular dystrophy 1 Diseases 0.000 description 1
- 208000021022 X-linked recessive inheritance Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000004234 Yellow 2G Substances 0.000 description 1
- JKQXZKUSFCKOGQ-LQFQNGICSA-N Z-zeaxanthin Natural products C([C@H](O)CC=1C)C(C)(C)C=1C=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-LQFQNGICSA-N 0.000 description 1
- QOPRSMDTRDMBNK-RNUUUQFGSA-N Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCC(O)C1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C QOPRSMDTRDMBNK-RNUUUQFGSA-N 0.000 description 1
- 235000006886 Zingiber officinale Nutrition 0.000 description 1
- 244000273928 Zingiber officinale Species 0.000 description 1
- 239000001940 [(1R,4S,6R)-1,7,7-trimethyl-6-bicyclo[2.2.1]heptanyl] acetate Substances 0.000 description 1
- NKWCOKZUKIEZAR-USWWRNFRSA-N [(1s,2r,3r)-1,2-dimethyl-3-prop-1-en-2-ylcyclopentyl] acetate Chemical compound C[C@@H]1[C@H](C(C)=C)CC[C@]1(C)OC(C)=O NKWCOKZUKIEZAR-USWWRNFRSA-N 0.000 description 1
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 description 1
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 239000001791 acetic acid esters of mono and diglycerides of fatty acids Substances 0.000 description 1
- 235000019431 acetylated distarch glycerol Nutrition 0.000 description 1
- 210000001361 achilles tendon Anatomy 0.000 description 1
- FUGCXLNGEHFIOA-UHFFFAOYSA-L acid red 44 Chemical compound [Na+].[Na+].C1=CC=C2C(N=NC3=C4C(=CC(=CC4=CC=C3O)S([O-])(=O)=O)S([O-])(=O)=O)=CC=CC2=C1 FUGCXLNGEHFIOA-UHFFFAOYSA-L 0.000 description 1
- 229920006397 acrylic thermoplastic Polymers 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 235000013829 acylated starch Nutrition 0.000 description 1
- 239000001339 acylated starch Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 229960000250 adipic acid Drugs 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229960004229 alclometasone dipropionate Drugs 0.000 description 1
- DJHCCTTVDRAMEH-DUUJBDRPSA-N alclometasone dipropionate Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O DJHCCTTVDRAMEH-DUUJBDRPSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000019409 alitame Nutrition 0.000 description 1
- 108010009985 alitame Proteins 0.000 description 1
- 235000019427 alkaline modified starch Nutrition 0.000 description 1
- 235000019232 alkannin Nutrition 0.000 description 1
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- ZVKOASAVGLETCT-UOAMSCJGSA-N all-trans norbixin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C(=O)O)C=CC=C(/C)C=CC(=O)O ZVKOASAVGLETCT-UOAMSCJGSA-N 0.000 description 1
- VWXMLZQUDPCJPL-JCFHCUBBSA-N all-trans-Rhodoxanthin Natural products CC(=C/C=C/C(=C/C=C/1C(=CC(=O)CC1(C)C)C)/C)C=CC=CC(=CC=CC(=CC=C2/C(=CC(=O)CC2(C)C)C)C)C VWXMLZQUDPCJPL-JCFHCUBBSA-N 0.000 description 1
- JKQXZKUSFCKOGQ-LOFNIBRQSA-N all-trans-Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C JKQXZKUSFCKOGQ-LOFNIBRQSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 235000012741 allura red AC Nutrition 0.000 description 1
- 239000004191 allura red AC Substances 0.000 description 1
- OOCCDEMITAIZTP-UHFFFAOYSA-N allylic benzylic alcohol Natural products OCC=CC1=CC=CC=C1 OOCCDEMITAIZTP-UHFFFAOYSA-N 0.000 description 1
- HMKKIXGYKWDQSV-KAMYIIQDSA-N alpha-Amylcinnamaldehyde Chemical compound CCCCC\C(C=O)=C\C1=CC=CC=C1 HMKKIXGYKWDQSV-KAMYIIQDSA-N 0.000 description 1
- RGZSQWQPBWRIAQ-LSDHHAIUSA-N alpha-Bisabolol Natural products CC(C)=CCC[C@@](C)(O)[C@@H]1CCC(C)=CC1 RGZSQWQPBWRIAQ-LSDHHAIUSA-N 0.000 description 1
- XCPQUQHBVVXMRQ-UHFFFAOYSA-N alpha-Fenchene Natural products C1CC2C(=C)CC1C2(C)C XCPQUQHBVVXMRQ-UHFFFAOYSA-N 0.000 description 1
- RAFGELQLHMBRHD-UHFFFAOYSA-N alpha-Fuc-(1-2)-beta-Gal-(1-3)-(beta-GlcNAc-(1-6))-GalNAc-ol Natural products COC(=O)C=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC(O)=O RAFGELQLHMBRHD-UHFFFAOYSA-N 0.000 description 1
- NQFUSWIGRKFAHK-BDNRQGISSA-N alpha-Pinene epoxide Natural products C([C@@H]1O[C@@]11C)[C@@H]2C(C)(C)[C@H]1C2 NQFUSWIGRKFAHK-BDNRQGISSA-N 0.000 description 1
- OVKDFILSBMEKLT-UHFFFAOYSA-N alpha-Terpineol Natural products CC(=C)C1(O)CCC(C)=CC1 OVKDFILSBMEKLT-UHFFFAOYSA-N 0.000 description 1
- OGCGGWYLHSJRFY-UHFFFAOYSA-N alpha-campholenic aldehyde Natural products CC1=CCC(CC=O)C1(C)C OGCGGWYLHSJRFY-UHFFFAOYSA-N 0.000 description 1
- 235000003903 alpha-carotene Nutrition 0.000 description 1
- 239000011795 alpha-carotene Substances 0.000 description 1
- ANVAOWXLWRTKGA-HLLMEWEMSA-N alpha-carotene Natural products C(=C\C=C\C=C(/C=C/C=C(\C=C\C=1C(C)(C)CCCC=1C)/C)\C)(\C=C\C=C(/C=C/[C@H]1C(C)=CCCC1(C)C)\C)/C ANVAOWXLWRTKGA-HLLMEWEMSA-N 0.000 description 1
- VYBREYKSZAROCT-UHFFFAOYSA-N alpha-myrcene Natural products CC(=C)CCCC(=C)C=C VYBREYKSZAROCT-UHFFFAOYSA-N 0.000 description 1
- OGLDWXZKYODSOB-SNVBAGLBSA-N alpha-phellandrene Natural products CC(C)[C@H]1CC=C(C)C=C1 OGLDWXZKYODSOB-SNVBAGLBSA-N 0.000 description 1
- MVNCAPSFBDBCGF-UHFFFAOYSA-N alpha-pinene Natural products CC1=CCC23C1CC2C3(C)C MVNCAPSFBDBCGF-UHFFFAOYSA-N 0.000 description 1
- 229930006723 alpha-pinene oxide Natural products 0.000 description 1
- 125000003425 alpha-pinene oxide group Chemical group 0.000 description 1
- WUOACPNHFRMFPN-UHFFFAOYSA-N alpha-terpineol Chemical compound CC1=CCC(C(C)(C)O)CC1 WUOACPNHFRMFPN-UHFFFAOYSA-N 0.000 description 1
- 229940088601 alpha-terpineol Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000010210 aluminium Nutrition 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 229940103272 aluminum potassium sulfate Drugs 0.000 description 1
- SXQXMCWCWVCFPC-UHFFFAOYSA-N aluminum;potassium;dioxido(oxo)silane Chemical compound [Al+3].[K+].[O-][Si]([O-])=O.[O-][Si]([O-])=O SXQXMCWCWVCFPC-UHFFFAOYSA-N 0.000 description 1
- 235000012735 amaranth Nutrition 0.000 description 1
- 239000004178 amaranth Substances 0.000 description 1
- 229960003099 amcinonide Drugs 0.000 description 1
- ILKJAFIWWBXGDU-MOGDOJJUSA-N amcinonide Chemical compound O([C@@]1([C@H](O2)C[C@@H]3[C@@]1(C[C@H](O)[C@]1(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]13)C)C(=O)COC(=O)C)C12CCCC1 ILKJAFIWWBXGDU-MOGDOJJUSA-N 0.000 description 1
- 235000019824 amidated pectin Nutrition 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000012706 ammonia caramel Nutrition 0.000 description 1
- 239000004125 ammonia caramel Substances 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019293 ammonium adipate Nutrition 0.000 description 1
- 235000010407 ammonium alginate Nutrition 0.000 description 1
- 239000000728 ammonium alginate Substances 0.000 description 1
- KPGABFJTMYCRHJ-YZOKENDUSA-N ammonium alginate Chemical compound [NH4+].[NH4+].O1[C@@H](C([O-])=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@@H](O)[C@H]1O KPGABFJTMYCRHJ-YZOKENDUSA-N 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- FRHBOQMZUOWXQL-UHFFFAOYSA-L ammonium ferric citrate Chemical compound [NH4+].[Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FRHBOQMZUOWXQL-UHFFFAOYSA-L 0.000 description 1
- 235000019297 ammonium fumarate Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 235000019286 ammonium lactate Nutrition 0.000 description 1
- 229940059265 ammonium lactate Drugs 0.000 description 1
- BTBJBAZGXNKLQC-UHFFFAOYSA-N ammonium lauryl sulfate Chemical compound [NH4+].CCCCCCCCCCCCOS([O-])(=O)=O BTBJBAZGXNKLQC-UHFFFAOYSA-N 0.000 description 1
- 229940063953 ammonium lauryl sulfate Drugs 0.000 description 1
- 235000019292 ammonium malate Nutrition 0.000 description 1
- KGECWXXIGSTYSQ-UHFFFAOYSA-N ammonium malate Chemical compound [NH4+].[NH4+].[O-]C(=O)C(O)CC([O-])=O KGECWXXIGSTYSQ-UHFFFAOYSA-N 0.000 description 1
- 239000001809 ammonium phosphatide Substances 0.000 description 1
- 235000010986 ammonium phosphatide Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 229940044197 ammonium sulfate Drugs 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 229940062909 amyl salicylate Drugs 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 229940011037 anethole Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000012874 anionic emulsifier Substances 0.000 description 1
- 210000003423 ankle Anatomy 0.000 description 1
- 239000010362 annatto Substances 0.000 description 1
- 235000010208 anthocyanin Nutrition 0.000 description 1
- 239000004410 anthocyanin Substances 0.000 description 1
- 229930002877 anthocyanin Natural products 0.000 description 1
- 150000004636 anthocyanins Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 201000009807 aspiration pneumonia Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 235000013793 astaxanthin Nutrition 0.000 description 1
- 239000001168 astaxanthin Substances 0.000 description 1
- MQZIGYBFDRPAKN-ZWAPEEGVSA-N astaxanthin Chemical compound C([C@H](O)C(=O)C=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C(=O)[C@@H](O)CC1(C)C MQZIGYBFDRPAKN-ZWAPEEGVSA-N 0.000 description 1
- 229940022405 astaxanthin Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000000527 autosomal recessive distal spinal muscular atrophy 1 Diseases 0.000 description 1
- 201000009563 autosomal recessive limb-girdle muscular dystrophy type 2B Diseases 0.000 description 1
- CKKXWJDFFQPBQL-SEPHDYHBSA-N azane;(e)-but-2-enedioic acid Chemical compound N.N.OC(=O)\C=C\C(O)=O CKKXWJDFFQPBQL-SEPHDYHBSA-N 0.000 description 1
- RZOBLYBZQXQGFY-HSHFZTNMSA-N azanium;(2r)-2-hydroxypropanoate Chemical compound [NH4+].C[C@@H](O)C([O-])=O RZOBLYBZQXQGFY-HSHFZTNMSA-N 0.000 description 1
- WXLFIFHRGFOVCD-UHFFFAOYSA-L azophloxine Chemical compound [Na+].[Na+].OC1=C2C(NC(=O)C)=CC(S([O-])(=O)=O)=CC2=CC(S([O-])(=O)=O)=C1N=NC1=CC=CC=C1 WXLFIFHRGFOVCD-UHFFFAOYSA-L 0.000 description 1
- 239000004176 azorubin Substances 0.000 description 1
- 235000012733 azorubine Nutrition 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229950000210 beclometasone dipropionate Drugs 0.000 description 1
- 229940092705 beclomethasone Drugs 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 235000012677 beetroot red Nutrition 0.000 description 1
- 239000001654 beetroot red Substances 0.000 description 1
- 229940116226 behenic acid Drugs 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940092782 bentonite Drugs 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229940007550 benzyl acetate Drugs 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 235000021028 berry Nutrition 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 108010051210 beta-Fructofuranosidase Proteins 0.000 description 1
- 235000013735 beta-apo-8'-carotenal Nutrition 0.000 description 1
- 239000001652 beta-apo-8'-carotenal Substances 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- 235000002360 beta-cryptoxanthin Nutrition 0.000 description 1
- DMASLKHVQRHNES-ITUXNECMSA-N beta-cryptoxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)CCCC2(C)C DMASLKHVQRHNES-ITUXNECMSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229930006722 beta-pinene Natural products 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 229960001102 betamethasone dipropionate Drugs 0.000 description 1
- CIWBQSYVNNPZIQ-XYWKZLDCSA-N betamethasone dipropionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CIWBQSYVNNPZIQ-XYWKZLDCSA-N 0.000 description 1
- 229960004311 betamethasone valerate Drugs 0.000 description 1
- SNHRLVCMMWUAJD-SUYDQAKGSA-N betamethasone valerate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O SNHRLVCMMWUAJD-SUYDQAKGSA-N 0.000 description 1
- 235000002185 betanin Nutrition 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- HHKZCCWKTZRCCL-UHFFFAOYSA-N bis-tris propane Chemical compound OCC(CO)(CO)NCCCNC(CO)(CO)CO HHKZCCWKTZRCCL-UHFFFAOYSA-N 0.000 description 1
- RAFGELQLHMBRHD-SLEZCNMESA-N bixin Chemical compound COC(=O)\C=C\C(\C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)/C=C/C(O)=O RAFGELQLHMBRHD-SLEZCNMESA-N 0.000 description 1
- 235000013614 black pepper Nutrition 0.000 description 1
- 235000019428 bleached starch Nutrition 0.000 description 1
- 235000021014 blueberries Nutrition 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 235000019347 bone phosphate Nutrition 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- ARTGXHJAOOHUMW-UHFFFAOYSA-N boric acid hydrate Chemical compound O.OB(O)O ARTGXHJAOOHUMW-UHFFFAOYSA-N 0.000 description 1
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 description 1
- 229940116229 borneol Drugs 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- 208000030303 breathing problems Diseases 0.000 description 1
- 235000012745 brilliant blue FCF Nutrition 0.000 description 1
- 239000004161 brilliant blue FCF Substances 0.000 description 1
- 229940055580 brilliant blue fcf Drugs 0.000 description 1
- 235000019835 bromelain Nutrition 0.000 description 1
- 235000019323 brominated vegetable oil Nutrition 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 235000012713 brown FK Nutrition 0.000 description 1
- 239000004109 brown FK Substances 0.000 description 1
- 235000012670 brown HT Nutrition 0.000 description 1
- 239000001678 brown HT Substances 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229950007227 buteprate Drugs 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 235000012215 calcium aluminium silicate Nutrition 0.000 description 1
- 239000000404 calcium aluminium silicate Substances 0.000 description 1
- WNCYAPRTYDMSFP-UHFFFAOYSA-N calcium aluminosilicate Chemical compound [Al+3].[Al+3].[Ca+2].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O WNCYAPRTYDMSFP-UHFFFAOYSA-N 0.000 description 1
- 229940078583 calcium aluminosilicate Drugs 0.000 description 1
- 235000010237 calcium benzoate Nutrition 0.000 description 1
- 239000004301 calcium benzoate Substances 0.000 description 1
- LVGQIQHJMRUCRM-UHFFFAOYSA-L calcium bisulfite Chemical compound [Ca+2].OS([O-])=O.OS([O-])=O LVGQIQHJMRUCRM-UHFFFAOYSA-L 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- 235000019815 calcium dihydrogen diphosphate Nutrition 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- JUNWLZAGQLJVLR-UHFFFAOYSA-J calcium diphosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])([O-])=O JUNWLZAGQLJVLR-UHFFFAOYSA-J 0.000 description 1
- 235000012251 calcium ferrocyanide Nutrition 0.000 description 1
- 239000000279 calcium ferrocyanide Substances 0.000 description 1
- 235000019255 calcium formate Nutrition 0.000 description 1
- 239000004281 calcium formate Substances 0.000 description 1
- 229940044172 calcium formate Drugs 0.000 description 1
- 235000019296 calcium fumarate Nutrition 0.000 description 1
- UHHRFSOMMCWGSO-UHFFFAOYSA-L calcium glycerophosphate Chemical compound [Ca+2].OCC(CO)OP([O-])([O-])=O UHHRFSOMMCWGSO-UHFFFAOYSA-L 0.000 description 1
- 229940095618 calcium glycerophosphate Drugs 0.000 description 1
- 235000019299 calcium glycerylphosphate Nutrition 0.000 description 1
- 235000013397 calcium hydrogen malate Nutrition 0.000 description 1
- 235000010260 calcium hydrogen sulphite Nutrition 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 239000001527 calcium lactate Substances 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- OLOZVPHKXALCRI-UHFFFAOYSA-L calcium malate Chemical compound [Ca+2].[O-]C(=O)C(O)CC([O-])=O OLOZVPHKXALCRI-UHFFFAOYSA-L 0.000 description 1
- 229940016114 calcium malate Drugs 0.000 description 1
- 235000011038 calcium malates Nutrition 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000010331 calcium propionate Nutrition 0.000 description 1
- 239000004330 calcium propionate Substances 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- 235000019348 calcium sodium polyphosphate Nutrition 0.000 description 1
- MCFVRESNTICQSJ-RJNTXXOISA-L calcium sorbate Chemical compound [Ca+2].C\C=C\C=C\C([O-])=O.C\C=C\C=C\C([O-])=O MCFVRESNTICQSJ-RJNTXXOISA-L 0.000 description 1
- 235000010244 calcium sorbate Nutrition 0.000 description 1
- 239000004303 calcium sorbate Substances 0.000 description 1
- OEUVSBXAMBLPES-UHFFFAOYSA-L calcium stearoyl-2-lactylate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC(=O)OC(C)C(=O)OC(C)C([O-])=O.CCCCCCCCCCCCCCCCCC(=O)OC(C)C(=O)OC(C)C([O-])=O OEUVSBXAMBLPES-UHFFFAOYSA-L 0.000 description 1
- 235000010957 calcium stearoyl-2-lactylate Nutrition 0.000 description 1
- 239000003916 calcium stearoyl-2-lactylate Substances 0.000 description 1
- GBAOBIBJACZTNA-UHFFFAOYSA-L calcium sulfite Chemical compound [Ca+2].[O-]S([O-])=O GBAOBIBJACZTNA-UHFFFAOYSA-L 0.000 description 1
- 235000010261 calcium sulphite Nutrition 0.000 description 1
- GUPPESBEIQALOS-UHFFFAOYSA-L calcium tartrate Chemical compound [Ca+2].[O-]C(=O)C(O)C(O)C([O-])=O GUPPESBEIQALOS-UHFFFAOYSA-L 0.000 description 1
- 235000011035 calcium tartrate Nutrition 0.000 description 1
- 239000001427 calcium tartrate Substances 0.000 description 1
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 1
- NVGFAQTYFPBKGP-UHFFFAOYSA-L calcium;3,4-dihydroxy-4-oxobutanoate Chemical compound [Ca+2].[O-]C(=O)C(O)CC(O)=O.[O-]C(=O)C(O)CC(O)=O NVGFAQTYFPBKGP-UHFFFAOYSA-L 0.000 description 1
- DIOLOCSXUMYFJN-UHFFFAOYSA-N calcium;azane Chemical compound N.[Ca+2] DIOLOCSXUMYFJN-UHFFFAOYSA-N 0.000 description 1
- HZQXCUSDXIKLGS-UHFFFAOYSA-L calcium;dibenzoate;trihydrate Chemical compound O.O.O.[Ca+2].[O-]C(=O)C1=CC=CC=C1.[O-]C(=O)C1=CC=CC=C1 HZQXCUSDXIKLGS-UHFFFAOYSA-L 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- VEJCUEBBRSCJRP-UHFFFAOYSA-L calcium;hydron;phosphonato phosphate Chemical compound [Ca+2].OP(O)(=O)OP([O-])([O-])=O VEJCUEBBRSCJRP-UHFFFAOYSA-L 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 239000001772 cananga odorata hook. f. and thomas. oil Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 235000012682 canthaxanthin Nutrition 0.000 description 1
- 239000001659 canthaxanthin Substances 0.000 description 1
- 229940008033 canthaxanthin Drugs 0.000 description 1
- 235000018889 capsanthin Nutrition 0.000 description 1
- WRANYHFEXGNSND-LOFNIBRQSA-N capsanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC(=O)C2(C)CCC(O)C2(C)C WRANYHFEXGNSND-LOFNIBRQSA-N 0.000 description 1
- 239000001325 capsicum annuum l. var. longum oleoresin Substances 0.000 description 1
- 235000009132 capsorubin Nutrition 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000006229 carbon black Substances 0.000 description 1
- 235000019241 carbon black Nutrition 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- UHBYWPGGCSDKFX-UHFFFAOYSA-N carboxyglutamic acid Chemical compound OC(=O)C(N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-UHFFFAOYSA-N 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 235000005300 cardamomo Nutrition 0.000 description 1
- 230000005800 cardiovascular problem Effects 0.000 description 1
- DGQLVPJVXFOQEV-NGOCYOHBSA-N carminic acid Chemical compound OC1=C2C(=O)C=3C(C)=C(C(O)=O)C(O)=CC=3C(=O)C2=C(O)C(O)=C1[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O DGQLVPJVXFOQEV-NGOCYOHBSA-N 0.000 description 1
- 229940114118 carminic acid Drugs 0.000 description 1
- 229940031019 carmoisine Drugs 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- HHTWOMMSBMNRKP-UHFFFAOYSA-N carvacrol Natural products CC(=C)C1=CC=C(C)C(O)=C1 HHTWOMMSBMNRKP-UHFFFAOYSA-N 0.000 description 1
- 235000007746 carvacrol Nutrition 0.000 description 1
- RECUKUPTGUEGMW-UHFFFAOYSA-N carvacrol Chemical compound CC(C)C1=CC=C(C)C(O)=C1 RECUKUPTGUEGMW-UHFFFAOYSA-N 0.000 description 1
- 229930007646 carveol Natural products 0.000 description 1
- ULDHMXUKGWMISQ-UHFFFAOYSA-N carvone Natural products CC(=C)C1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-UHFFFAOYSA-N 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 235000012704 caustic sulphite caramel Nutrition 0.000 description 1
- 239000004123 caustic sulphite caramel Substances 0.000 description 1
- 150000001783 ceramides Chemical class 0.000 description 1
- 159000000006 cesium salts Chemical class 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 239000007958 cherry flavor Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000019398 chlorine dioxide Nutrition 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 239000001752 chlorophylls and chlorophyllins Substances 0.000 description 1
- 235000012698 chlorophylls and chlorophyllins Nutrition 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 235000019417 choline salt Nutrition 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 229960003728 ciclesonide Drugs 0.000 description 1
- 229930007050 cineol Natural products 0.000 description 1
- 229940117916 cinnamic aldehyde Drugs 0.000 description 1
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 1
- 235000017803 cinnamon Nutrition 0.000 description 1
- BJIOGJUNALELMI-ARJAWSKDSA-N cis-isoeugenol Chemical compound COC1=CC(\C=C/C)=CC=C1O BJIOGJUNALELMI-ARJAWSKDSA-N 0.000 description 1
- 229940043350 citral Drugs 0.000 description 1
- 235000019247 citranaxanthin Nutrition 0.000 description 1
- PRDJTOVRIHGKNU-ZWERVMMHSA-N citranaxanthin Chemical compound CC(=O)\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C PRDJTOVRIHGKNU-ZWERVMMHSA-N 0.000 description 1
- PRDJTOVRIHGKNU-UHFFFAOYSA-N citranaxanthine Natural products CC(=O)C=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C PRDJTOVRIHGKNU-UHFFFAOYSA-N 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 235000000983 citronellal Nutrition 0.000 description 1
- 229930003633 citronellal Natural products 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 235000013986 citrus red 2 Nutrition 0.000 description 1
- 239000001679 citrus red 2 Substances 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229960004703 clobetasol propionate Drugs 0.000 description 1
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 description 1
- 229960005465 clobetasone butyrate Drugs 0.000 description 1
- 238000005354 coacervation Methods 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 229940080423 cochineal Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000001609 comparable effect Effects 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 208000006111 contracture Diseases 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000004121 copper complexes of chlorophylls and chlorophyllins Substances 0.000 description 1
- 235000012700 copper complexes of chlorophylls and chlorophyllins Nutrition 0.000 description 1
- BMCQMVFGOVHVNG-TUFAYURCSA-N cortisol 17-butyrate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O BMCQMVFGOVHVNG-TUFAYURCSA-N 0.000 description 1
- FZCHYNWYXKICIO-FZNHGJLXSA-N cortisol 17-valerate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O FZCHYNWYXKICIO-FZNHGJLXSA-N 0.000 description 1
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 229960003290 cortisone acetate Drugs 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 235000004634 cranberry Nutrition 0.000 description 1
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 1
- 150000001896 cresols Chemical class 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000019244 cryptoxanthin Nutrition 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 235000003373 curcuma longa Nutrition 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960001987 dantrolene Drugs 0.000 description 1
- SASYSVUEVMOWPL-NXVVXOECSA-N decyl oleate Chemical compound CCCCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC SASYSVUEVMOWPL-NXVVXOECSA-N 0.000 description 1
- 239000013530 defoamer Substances 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- SQIFACVGCPWBQZ-UHFFFAOYSA-N delta-terpineol Natural products CC(C)(O)C1CCC(=C)CC1 SQIFACVGCPWBQZ-UHFFFAOYSA-N 0.000 description 1
- 229940027008 deltasone Drugs 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229960003662 desonide Drugs 0.000 description 1
- WBGKWQHBNHJJPZ-LECWWXJVSA-N desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000019821 dicalcium diphosphate Nutrition 0.000 description 1
- 229910000393 dicalcium diphosphate Inorganic materials 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 229930007024 dihydrocarveol Natural products 0.000 description 1
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 1
- XSNQECSCDATQEL-UHFFFAOYSA-N dihydromyrcenol Chemical compound C=CC(C)CCCC(C)(C)O XSNQECSCDATQEL-UHFFFAOYSA-N 0.000 description 1
- 229930008394 dihydromyrcenol Natural products 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 description 1
- DVUATXGAAOINPS-UHFFFAOYSA-N dimethoxyarsinic acid Chemical compound CO[As](O)(=O)OC DVUATXGAAOINPS-UHFFFAOYSA-N 0.000 description 1
- 235000010300 dimethyl dicarbonate Nutrition 0.000 description 1
- 239000004316 dimethyl dicarbonate Substances 0.000 description 1
- OGGXGZAMXPVRFZ-UHFFFAOYSA-M dimethylarsinate Chemical compound C[As](C)([O-])=O OGGXGZAMXPVRFZ-UHFFFAOYSA-M 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- 235000016693 dipotassium tartrate Nutrition 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- WPUMTJGUQUYPIV-JIZZDEOASA-L disodium (S)-malate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)CC([O-])=O WPUMTJGUQUYPIV-JIZZDEOASA-L 0.000 description 1
- MSJMDZAOKORVFC-SEPHDYHBSA-L disodium fumarate Chemical compound [Na+].[Na+].[O-]C(=O)\C=C\C([O-])=O MSJMDZAOKORVFC-SEPHDYHBSA-L 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019524 disodium tartrate Nutrition 0.000 description 1
- SMVRDGHCVNAOIN-UHFFFAOYSA-L disodium;1-dodecoxydodecane;sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O.CCCCCCCCCCCCOCCCCCCCCCCCC SMVRDGHCVNAOIN-UHFFFAOYSA-L 0.000 description 1
- FTZLWXQKVFFWLY-UHFFFAOYSA-L disodium;2,5-dichloro-4-[3-methyl-5-oxo-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazol-1-yl]benzenesulfonate Chemical compound [Na+].[Na+].CC1=NN(C=2C(=CC(=C(Cl)C=2)S([O-])(=O)=O)Cl)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 FTZLWXQKVFFWLY-UHFFFAOYSA-L 0.000 description 1
- UQGFMSUEHSUPRD-UHFFFAOYSA-N disodium;3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane Chemical compound [Na+].[Na+].O1B([O-])OB2OB([O-])OB1O2 UQGFMSUEHSUPRD-UHFFFAOYSA-N 0.000 description 1
- TUQJHVRCALPCHU-QPRXZMCZSA-L disodium;4-[(2z)-2-[(5e)-3-(hydroxymethyl)-4,6-dioxo-5-[(4-sulfonatonaphthalen-1-yl)hydrazinylidene]cyclohex-2-en-1-ylidene]hydrazinyl]naphthalene-1-sulfonate Chemical compound [Na+].[Na+].C1=CC=C2C(N/N=C3/C(=O)C(=N\NC=4C5=CC=CC=C5C(=CC=4)S([O-])(=O)=O)/C=C(C3=O)CO)=CC=C(S([O-])(=O)=O)C2=C1 TUQJHVRCALPCHU-QPRXZMCZSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 208000021347 distal spinal muscular atrophy 1 Diseases 0.000 description 1
- 235000019429 distarch glycerol Nutrition 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 description 1
- HSMMSDWNEJLVRY-INIZCTEOSA-N dodecyl (2s)-2-(dimethylamino)propanoate Chemical compound CCCCCCCCCCCCOC(=O)[C@H](C)N(C)C HSMMSDWNEJLVRY-INIZCTEOSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 235000014134 echinacea Nutrition 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 108010056197 emerin Proteins 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- IINNWAYUJNWZRM-UHFFFAOYSA-L erythrosin B Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 IINNWAYUJNWZRM-UHFFFAOYSA-L 0.000 description 1
- 235000012732 erythrosine Nutrition 0.000 description 1
- 239000004174 erythrosine Substances 0.000 description 1
- 229940011411 erythrosine Drugs 0.000 description 1
- 229950005470 eteplirsen Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- NYNCZOLNVTXTTP-UHFFFAOYSA-N ethyl 2-(1,3-dioxoisoindol-2-yl)acetate Chemical compound C1=CC=C2C(=O)N(CC(=O)OCC)C(=O)C2=C1 NYNCZOLNVTXTTP-UHFFFAOYSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000012656 ethyl ester of beta-apo-8'-carotenic acid Nutrition 0.000 description 1
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 1
- 239000001761 ethyl methyl cellulose Substances 0.000 description 1
- 229940073505 ethyl vanillin Drugs 0.000 description 1
- HXQVQGWHFRNKMS-UHFFFAOYSA-M ethylmercurithiosalicylic acid Chemical compound CC[Hg]SC1=CC=CC=C1C(O)=O HXQVQGWHFRNKMS-UHFFFAOYSA-M 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 229960002217 eugenol Drugs 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 235000019240 fast green FCF Nutrition 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 210000003746 feather Anatomy 0.000 description 1
- RAQDACVRFCEPDA-UHFFFAOYSA-L ferrous carbonate Chemical compound [Fe+2].[O-]C([O-])=O RAQDACVRFCEPDA-UHFFFAOYSA-L 0.000 description 1
- 235000019268 ferrous carbonate Nutrition 0.000 description 1
- 229960004652 ferrous carbonate Drugs 0.000 description 1
- 235000013924 ferrous gluconate Nutrition 0.000 description 1
- 239000004222 ferrous gluconate Substances 0.000 description 1
- 229960001645 ferrous gluconate Drugs 0.000 description 1
- 235000013925 ferrous lactate Nutrition 0.000 description 1
- 239000004225 ferrous lactate Substances 0.000 description 1
- 229940037907 ferrous lactate Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 235000019836 ficin Nutrition 0.000 description 1
- POTUGHMKJGOKRI-UHFFFAOYSA-N ficin Chemical compound FI=CI=N POTUGHMKJGOKRI-UHFFFAOYSA-N 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 description 1
- 239000011768 flavin mononucleotide Substances 0.000 description 1
- 235000019243 flavoxanthin Nutrition 0.000 description 1
- 235000004426 flaxseed Nutrition 0.000 description 1
- 229960003469 flumetasone Drugs 0.000 description 1
- WXURHACBFYSXBI-GQKYHHCASA-N flumethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-GQKYHHCASA-N 0.000 description 1
- 229960000676 flunisolide Drugs 0.000 description 1
- 229940043075 fluocinolone Drugs 0.000 description 1
- 229960000785 fluocinonide Drugs 0.000 description 1
- 229960003973 fluocortolone Drugs 0.000 description 1
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N fluocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 description 1
- 229960004437 fluocortolone caproate Drugs 0.000 description 1
- 229960005283 fluocortolone pivalate Drugs 0.000 description 1
- XZBJVIQXJHGUBE-HZMVJJPJSA-N fluocortolone pivalate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)COC(=O)C(C)(C)C)[C@@]2(C)C[C@@H]1O XZBJVIQXJHGUBE-HZMVJJPJSA-N 0.000 description 1
- 229960002650 fluprednidene acetate Drugs 0.000 description 1
- DEFOZIFYUBUHHU-IYQKUMFPSA-N fluprednidene acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC(=C)[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O DEFOZIFYUBUHHU-IYQKUMFPSA-N 0.000 description 1
- 229960001469 fluticasone furoate Drugs 0.000 description 1
- XTULMSXFIHGYFS-VLSRWLAYSA-N fluticasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4[C@@H](F)C[C@H]3[C@@H]2C[C@H]1C)C(=O)SCF)C(=O)C1=CC=CO1 XTULMSXFIHGYFS-VLSRWLAYSA-N 0.000 description 1
- 229960000289 fluticasone propionate Drugs 0.000 description 1
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000000576 food coloring agent Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 229940044170 formate Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940013688 formic acid Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- ONKNPOPIGWHAQC-UHFFFAOYSA-N galaxolide Chemical compound C1OCC(C)C2=C1C=C1C(C)(C)C(C)C(C)(C)C1=C2 ONKNPOPIGWHAQC-UHFFFAOYSA-N 0.000 description 1
- LCWMKIHBLJLORW-UHFFFAOYSA-N gamma-carene Natural products C1CC(=C)CC2C(C)(C)C21 LCWMKIHBLJLORW-UHFFFAOYSA-N 0.000 description 1
- 235000000633 gamma-carotene Nutrition 0.000 description 1
- 239000011663 gamma-carotene Substances 0.000 description 1
- HRQKOYFGHJYEFS-RZWPOVEWSA-N gamma-carotene Natural products C(=C\C=C\C(=C/C=C/C=C(\C=C\C=C(/C=C/C=1C(C)(C)CCCC=1C)\C)/C)\C)(\C=C\C=C(/CC/C=C(\C)/C)\C)/C HRQKOYFGHJYEFS-RZWPOVEWSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000010492 gellan gum Nutrition 0.000 description 1
- 239000000216 gellan gum Substances 0.000 description 1
- 238000010457 gene scissor Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- WTEVQBCEXWBHNA-JXMROGBWSA-N geranial Chemical compound CC(C)=CCC\C(C)=C\C=O WTEVQBCEXWBHNA-JXMROGBWSA-N 0.000 description 1
- 229940113087 geraniol Drugs 0.000 description 1
- HNZUNIKWNYHEJJ-UHFFFAOYSA-N geranyl acetone Natural products CC(C)=CCCC(C)=CCCC(C)=O HNZUNIKWNYHEJJ-UHFFFAOYSA-N 0.000 description 1
- 235000008397 ginger Nutrition 0.000 description 1
- 229940046240 glucomannan Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 239000001806 glycerol esters of wood rosin Substances 0.000 description 1
- 235000010985 glycerol esters of wood rosin Nutrition 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- 229940043257 glycylglycine Drugs 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 231100000001 growth retardation Toxicity 0.000 description 1
- 229960001867 guaiacol Drugs 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 235000019314 gum ghatti Nutrition 0.000 description 1
- 229960002383 halcinonide Drugs 0.000 description 1
- 229960002475 halometasone Drugs 0.000 description 1
- GGXMRPUKBWXVHE-MIHLVHIWSA-N halometasone Chemical compound C1([C@@H](F)C2)=CC(=O)C(Cl)=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O GGXMRPUKBWXVHE-MIHLVHIWSA-N 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- KWLMIXQRALPRBC-UHFFFAOYSA-L hectorite Chemical compound [Li+].[OH-].[OH-].[Na+].[Mg+2].O1[Si]2([O-])O[Si]1([O-])O[Si]([O-])(O1)O[Si]1([O-])O2 KWLMIXQRALPRBC-UHFFFAOYSA-L 0.000 description 1
- 229910000271 hectorite Inorganic materials 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 235000019251 heptyl p-hydroxybenzoate Nutrition 0.000 description 1
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 1
- 239000004312 hexamethylene tetramine Substances 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 210000002758 humerus Anatomy 0.000 description 1
- 229960001067 hydrocortisone acetate Drugs 0.000 description 1
- 229960001524 hydrocortisone butyrate Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 235000019434 hydroxy propyl distarch glycerol Nutrition 0.000 description 1
- DVROLKBAWTYHHD-UHFFFAOYSA-N hydroxy propyl distarch phosphate Chemical compound OC1C(O)C(OC)OC(CO)C1OC(O)CCOC1C(OC2C(C(O)C(OC3C(C(OP(O)(=O)OC4C(C(O)C(OC)OC4CO)O)C(C)OC3CO)O)OC2COC2C(C(O)C(OC)C(CO)O2)O)O)OC(CO)C(OC)C1O DVROLKBAWTYHHD-UHFFFAOYSA-N 0.000 description 1
- 235000013825 hydroxy propyl distarch phosphate Nutrition 0.000 description 1
- 239000001310 hydroxy propyl distarch phosphate Substances 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- VLHZUYUOEGBBJB-UHFFFAOYSA-N hydroxy stearic acid Natural products OCCCCCCCCCCCCCCCCCC(O)=O VLHZUYUOEGBBJB-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- WPFVBOQKRVRMJB-UHFFFAOYSA-N hydroxycitronellal Chemical compound O=CCC(C)CCCC(C)(C)O WPFVBOQKRVRMJB-UHFFFAOYSA-N 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- NBZBKCUXIYYUSX-UHFFFAOYSA-N iminodiacetic acid Chemical compound OC(=O)CNCC(O)=O NBZBKCUXIYYUSX-UHFFFAOYSA-N 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 229940124622 immune-modulator drug Drugs 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 235000019239 indanthrene blue RS Nutrition 0.000 description 1
- UHOKSCJSTAHBSO-UHFFFAOYSA-N indanthrone blue Chemical compound C1=CC=C2C(=O)C3=CC=C4NC5=C6C(=O)C7=CC=CC=C7C(=O)C6=CC=C5NC4=C3C(=O)C2=C1 UHOKSCJSTAHBSO-UHFFFAOYSA-N 0.000 description 1
- KHLVKKOJDHCJMG-QDBORUFSSA-L indigo carmine Chemical compound [Na+].[Na+].N/1C2=CC=C(S([O-])(=O)=O)C=C2C(=O)C\1=C1/NC2=CC=C(S(=O)(=O)[O-])C=C2C1=O KHLVKKOJDHCJMG-QDBORUFSSA-L 0.000 description 1
- 229960003988 indigo carmine Drugs 0.000 description 1
- 235000012738 indigotine Nutrition 0.000 description 1
- 239000004179 indigotine Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000003434 inspiratory effect Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 235000011073 invertase Nutrition 0.000 description 1
- 239000001573 invertase Substances 0.000 description 1
- 229930002839 ionone Natural products 0.000 description 1
- 150000002499 ionone derivatives Chemical class 0.000 description 1
- 244000023249 iris florentino Species 0.000 description 1
- 235000000011 iron ammonium citrate Nutrition 0.000 description 1
- 239000004313 iron ammonium citrate Substances 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- 235000013980 iron oxide Nutrition 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- 229910000015 iron(II) carbonate Inorganic materials 0.000 description 1
- VRIVJOXICYMTAG-IYEMJOQQSA-L iron(ii) gluconate Chemical compound [Fe+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O VRIVJOXICYMTAG-IYEMJOQQSA-L 0.000 description 1
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical class [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- WYXXLXHHWYNKJF-UHFFFAOYSA-N isocarvacrol Natural products CC(C)C1=CC=C(O)C(C)=C1 WYXXLXHHWYNKJF-UHFFFAOYSA-N 0.000 description 1
- 229960002857 isoflupredone Drugs 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 239000000905 isomalt Substances 0.000 description 1
- 235000010439 isomalt Nutrition 0.000 description 1
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 1
- 235000019300 isopropyl citrate Nutrition 0.000 description 1
- SKHXHUZZFVMERR-UHFFFAOYSA-L isopropyl citrate Chemical compound CC(C)OC(=O)CC(O)(C([O-])=O)CC([O-])=O SKHXHUZZFVMERR-UHFFFAOYSA-L 0.000 description 1
- 201000004815 juvenile spinal muscular atrophy Diseases 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- 239000000231 karaya gum Substances 0.000 description 1
- 229940039371 karaya gum Drugs 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000001792 lactic acid esters of mono and diglycerides of fatty acids Substances 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019328 lactylated fatty acid esters of glycerol and propane-1 Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 229960003639 laurocapram Drugs 0.000 description 1
- 239000000171 lavandula angustifolia l. flower oil Substances 0.000 description 1
- 239000001102 lavandula vera Substances 0.000 description 1
- 235000018219 lavender Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229940059904 light mineral oil Drugs 0.000 description 1
- 208000027905 limb weakness Diseases 0.000 description 1
- 231100000861 limb weakness Toxicity 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 229930007744 linalool Natural products 0.000 description 1
- UWKAYLJWKGQEPM-UHFFFAOYSA-N linalool acetate Natural products CC(C)=CCCC(C)(C=C)OC(C)=O UWKAYLJWKGQEPM-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960001078 lithium Drugs 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 235000010187 litholrubine BK Nutrition 0.000 description 1
- 239000004335 litholrubine BK Substances 0.000 description 1
- 208000018883 loss of balance Diseases 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 235000012680 lutein Nutrition 0.000 description 1
- 239000001656 lutein Substances 0.000 description 1
- 229960005375 lutein Drugs 0.000 description 1
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 description 1
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 description 1
- 235000012661 lycopene Nutrition 0.000 description 1
- 239000001751 lycopene Substances 0.000 description 1
- 229960004999 lycopene Drugs 0.000 description 1
- OAIJSZIZWZSQBC-GYZMGTAESA-N lycopene Chemical compound CC(C)=CCC\C(C)=C\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C=C(/C)CCC=C(C)C OAIJSZIZWZSQBC-GYZMGTAESA-N 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- QWDJLDTYWNBUKE-UHFFFAOYSA-L magnesium bicarbonate Chemical compound [Mg+2].OC([O-])=O.OC([O-])=O QWDJLDTYWNBUKE-UHFFFAOYSA-L 0.000 description 1
- 239000002370 magnesium bicarbonate Substances 0.000 description 1
- 235000014824 magnesium bicarbonate Nutrition 0.000 description 1
- 229910000022 magnesium bicarbonate Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000004337 magnesium citrate Substances 0.000 description 1
- 235000002538 magnesium citrate Nutrition 0.000 description 1
- 229960005336 magnesium citrate Drugs 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- OVGXLJDWSLQDRT-UHFFFAOYSA-L magnesium lactate Chemical compound [Mg+2].CC(O)C([O-])=O.CC(O)C([O-])=O OVGXLJDWSLQDRT-UHFFFAOYSA-L 0.000 description 1
- 235000015229 magnesium lactate Nutrition 0.000 description 1
- 239000000626 magnesium lactate Substances 0.000 description 1
- 229960004658 magnesium lactate Drugs 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 239000000457 mentha pulegium l. herb oil Substances 0.000 description 1
- 229930007503 menthone Natural products 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 235000011042 metatartaric acid Nutrition 0.000 description 1
- 239000001369 metatartaric acid Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229960004011 methenamine Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 235000006109 methionine Nutrition 0.000 description 1
- 229940102398 methyl anthranilate Drugs 0.000 description 1
- 235000019335 methyl glucoside-coconut oil ester Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960003404 mexiletine Drugs 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 210000003632 microfilament Anatomy 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000002273 mixed acetic and tartraric acid esters of mono and diglycerides of fatty acids Substances 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 229960002744 mometasone furoate Drugs 0.000 description 1
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 description 1
- 239000001937 mono and diacetyl tartraric acid esters of mono and diglycerides of fatty acids Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 235000013807 monostarch phosphate Nutrition 0.000 description 1
- 239000001248 monostarch phosphate Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 206010028320 muscle necrosis Diseases 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 229940067137 musk ketone Drugs 0.000 description 1
- XMWRWTSZNLOZFN-UHFFFAOYSA-N musk xylene Chemical compound CC1=C(N(=O)=O)C(C)=C(N(=O)=O)C(C(C)(C)C)=C1N(=O)=O XMWRWTSZNLOZFN-UHFFFAOYSA-N 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 210000003365 myofibril Anatomy 0.000 description 1
- 238000001885 myotomy Methods 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 235000010298 natamycin Nutrition 0.000 description 1
- 239000004311 natamycin Substances 0.000 description 1
- NCXMLFZGDNKEPB-FFPOYIOWSA-N natamycin Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C[C@@H](C)OC(=O)/C=C/[C@H]2O[C@@H]2C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 NCXMLFZGDNKEPB-FFPOYIOWSA-N 0.000 description 1
- 229960003255 natamycin Drugs 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- ITVGXXMINPYUHD-CUVHLRMHSA-N neohesperidin dihydrochalcone Chemical compound C1=C(O)C(OC)=CC=C1CCC(=O)C(C(=C1)O)=C(O)C=C1O[C@H]1[C@H](O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 ITVGXXMINPYUHD-CUVHLRMHSA-N 0.000 description 1
- 239000000879 neohesperidine DC Substances 0.000 description 1
- 235000019412 neotame Nutrition 0.000 description 1
- HLIAVLHNDJUHFG-HOTGVXAUSA-N neotame Chemical compound CC(C)(C)CCN[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 HLIAVLHNDJUHFG-HOTGVXAUSA-N 0.000 description 1
- 108010070257 neotame Proteins 0.000 description 1
- HIGQPQRQIQDZMP-FLIBITNWSA-N neryl acetate Chemical compound CC(C)=CCC\C(C)=C/COC(C)=O HIGQPQRQIQDZMP-FLIBITNWSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000010297 nisin Nutrition 0.000 description 1
- 239000004309 nisin Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012875 nonionic emulsifier Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229950001015 nusinersen Drugs 0.000 description 1
- 239000001702 nutmeg Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 235000019313 oat gum Nutrition 0.000 description 1
- 239000001912 oat gum Substances 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 238000001584 occupational therapy Methods 0.000 description 1
- 229940060184 oil ingredients Drugs 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 235000019236 orange GGN Nutrition 0.000 description 1
- CECHAJXICNIUQL-QIKYXUGXSA-L orange ggn Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1\N=N\C1=CC=CC(S([O-])(=O)=O)=C1 CECHAJXICNIUQL-QIKYXUGXSA-L 0.000 description 1
- 235000019248 orcein Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 235000010292 orthophenyl phenol Nutrition 0.000 description 1
- 239000004306 orthophenyl phenol Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- ZDYUUBIMAGBMPY-UHFFFAOYSA-N oxalic acid;hydrate Chemical compound O.OC(=O)C(O)=O ZDYUUBIMAGBMPY-UHFFFAOYSA-N 0.000 description 1
- FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 235000013808 oxidized starch Nutrition 0.000 description 1
- 239000001254 oxidized starch Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 235000019302 oxystearin Nutrition 0.000 description 1
- CFJYNSNXFXLKNS-UHFFFAOYSA-N p-menthane Chemical compound CC(C)C1CCC(C)CC1 CFJYNSNXFXLKNS-UHFFFAOYSA-N 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- DYUUPIKEWLHQGQ-SDXBLLFJSA-N paprika oleoresin Chemical compound C(\[C@]12[C@@](O1)(C)C[C@@H](O)CC2(C)C)=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=C[C@H]1C(C)=C[C@H](O)CC1(C)C DYUUPIKEWLHQGQ-SDXBLLFJSA-N 0.000 description 1
- RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 208000012318 pareses Diseases 0.000 description 1
- 235000012736 patent blue V Nutrition 0.000 description 1
- 239000004177 patent blue V Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000003415 peat Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000019831 pentapotassium triphosphate Nutrition 0.000 description 1
- ATGAWOHQWWULNK-UHFFFAOYSA-I pentapotassium;[oxido(phosphonatooxy)phosphoryl] phosphate Chemical compound [K+].[K+].[K+].[K+].[K+].[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O ATGAWOHQWWULNK-UHFFFAOYSA-I 0.000 description 1
- HWGNBUXHKFFFIH-UHFFFAOYSA-I pentasodium;[oxido(phosphonatooxy)phosphoryl] phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O HWGNBUXHKFFFIH-UHFFFAOYSA-I 0.000 description 1
- 201000001245 periodontitis Diseases 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008017 pharmaceutical colorant Substances 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- FHSWXOCOMAVQKE-UHFFFAOYSA-N phenylazanium;acetate Chemical compound CC([O-])=O.[NH3+]C1=CC=CC=C1 FHSWXOCOMAVQKE-UHFFFAOYSA-N 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- PZTQVMXMKVTIRC-RZLHGTIFSA-L pigment rubine Chemical compound [Ca+2].[O-]S(=O)(=O)C1=CC(C)=CC=C1\N=N\C1=C(O)C(C([O-])=O)=CC2=CC=CC=C12 PZTQVMXMKVTIRC-RZLHGTIFSA-L 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- XOKSLPVRUOBDEW-UHFFFAOYSA-N pinane of uncertain configuration Natural products CC1CCC2C(C)(C)C1C2 XOKSLPVRUOBDEW-UHFFFAOYSA-N 0.000 description 1
- 239000001739 pinus spp. Substances 0.000 description 1
- 229940081310 piperonal Drugs 0.000 description 1
- 235000012703 plain caramel Nutrition 0.000 description 1
- 239000004122 plain caramel Substances 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920000223 polyglycerol Polymers 0.000 description 1
- 235000010958 polyglycerol polyricinoleate Nutrition 0.000 description 1
- 239000003996 polyglycerol polyricinoleate Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920005606 polypropylene copolymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000012731 ponceau 4R Nutrition 0.000 description 1
- 239000004175 ponceau 4R Substances 0.000 description 1
- 235000019238 ponceau 6R Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- AVTYONGGKAJVTE-OLXYHTOASA-L potassium L-tartrate Chemical compound [K+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O AVTYONGGKAJVTE-OLXYHTOASA-L 0.000 description 1
- GCHCGDFZHOEXMP-UHFFFAOYSA-L potassium adipate Chemical compound [K+].[K+].[O-]C(=O)CCCCC([O-])=O GCHCGDFZHOEXMP-UHFFFAOYSA-L 0.000 description 1
- 239000001608 potassium adipate Substances 0.000 description 1
- 235000011051 potassium adipate Nutrition 0.000 description 1
- 235000010408 potassium alginate Nutrition 0.000 description 1
- 239000000737 potassium alginate Substances 0.000 description 1
- MZYRDLHIWXQJCQ-YZOKENDUSA-L potassium alginate Chemical compound [K+].[K+].O1[C@@H](C([O-])=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@@H](O)[C@H]1O MZYRDLHIWXQJCQ-YZOKENDUSA-L 0.000 description 1
- GRLPQNLYRHEGIJ-UHFFFAOYSA-J potassium aluminium sulfate Chemical compound [Al+3].[K+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O GRLPQNLYRHEGIJ-UHFFFAOYSA-J 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 235000010235 potassium benzoate Nutrition 0.000 description 1
- 239000004300 potassium benzoate Substances 0.000 description 1
- 229940103091 potassium benzoate Drugs 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000000276 potassium ferrocyanide Substances 0.000 description 1
- 235000012249 potassium ferrocyanide Nutrition 0.000 description 1
- SHPKCSFVQGSAJU-SEPHDYHBSA-L potassium fumarate Chemical compound [K+].[K+].[O-]C(=O)\C=C\C([O-])=O SHPKCSFVQGSAJU-SEPHDYHBSA-L 0.000 description 1
- 235000019295 potassium fumarate Nutrition 0.000 description 1
- 235000010259 potassium hydrogen sulphite Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- PHZLMBHDXVLRIX-UHFFFAOYSA-M potassium lactate Chemical compound [K+].CC(O)C([O-])=O PHZLMBHDXVLRIX-UHFFFAOYSA-M 0.000 description 1
- 235000011085 potassium lactate Nutrition 0.000 description 1
- 239000001521 potassium lactate Substances 0.000 description 1
- 229960001304 potassium lactate Drugs 0.000 description 1
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 1
- 229940043349 potassium metabisulfite Drugs 0.000 description 1
- 235000010263 potassium metabisulphite Nutrition 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010289 potassium nitrite Nutrition 0.000 description 1
- 239000004304 potassium nitrite Substances 0.000 description 1
- BWILYWWHXDGKQA-UHFFFAOYSA-M potassium propanoate Chemical compound [K+].CCC([O-])=O BWILYWWHXDGKQA-UHFFFAOYSA-M 0.000 description 1
- 235000010332 potassium propionate Nutrition 0.000 description 1
- 239000004331 potassium propionate Substances 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 229940114930 potassium stearate Drugs 0.000 description 1
- BHZRJJOHZFYXTO-UHFFFAOYSA-L potassium sulfite Chemical compound [K+].[K+].[O-]S([O-])=O BHZRJJOHZFYXTO-UHFFFAOYSA-L 0.000 description 1
- 235000019252 potassium sulphite Nutrition 0.000 description 1
- 239000001472 potassium tartrate Substances 0.000 description 1
- ANBFRLKBEIFNQU-UHFFFAOYSA-M potassium;octadecanoate Chemical compound [K+].CCCCCCCCCCCCCCCCCC([O-])=O ANBFRLKBEIFNQU-UHFFFAOYSA-M 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 229960002794 prednicarbate Drugs 0.000 description 1
- FNPXMHRZILFCKX-KAJVQRHHSA-N prednicarbate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CC)(OC(=O)OCC)[C@@]1(C)C[C@@H]2O FNPXMHRZILFCKX-KAJVQRHHSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 235000010421 processed eucheuma seaweed Nutrition 0.000 description 1
- 239000000640 processed eucheuma seaweed Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000013930 proline Nutrition 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- 239000000770 propane-1,2-diol alginate Substances 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- JXJIQCXXJGRKRJ-KOOBJXAQSA-N pseudoionone Chemical compound CC(C)=CCC\C(C)=C\C=C\C(C)=O JXJIQCXXJGRKRJ-KOOBJXAQSA-N 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 210000004879 pulmonary tissue Anatomy 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 1
- 239000001300 quillaia extract Substances 0.000 description 1
- 235000013852 quillaia extract Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960005038 quinisocaine Drugs 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 238000002278 reconstructive surgery Methods 0.000 description 1
- 235000012739 red 2G Nutrition 0.000 description 1
- 239000004180 red 2G Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000003019 respiratory muscle Anatomy 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 235000019246 rhodoxanthin Nutrition 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 235000019231 riboflavin-5'-phosphate Nutrition 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229940121322 risdiplam Drugs 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 235000009514 rubixanthin Nutrition 0.000 description 1
- 239000000455 rubixanthin Substances 0.000 description 1
- ABTRFGSPYXCGMR-SDPRXREBSA-N rubixanthin Natural products O[C@H]1CC(C)(C)C(/C=C/C(=C\C=C\C(=C/C=C/C=C(\C=C\C=C(/C=C/C=C(\CC/C=C(\C)/C)/C)\C)/C)\C)/C)=C(C)C1 ABTRFGSPYXCGMR-SDPRXREBSA-N 0.000 description 1
- 235000010437 saccharin and its sodium, potassium and calcium salts Nutrition 0.000 description 1
- 235000013974 saffron Nutrition 0.000 description 1
- 239000004248 saffron Substances 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 210000000518 sarcolemma Anatomy 0.000 description 1
- 208000001076 sarcopenia Diseases 0.000 description 1
- 210000001991 scapula Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- 210000002363 skeletal muscle cell Anatomy 0.000 description 1
- 235000019265 sodium DL-malate Nutrition 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- KYKFCSHPTAVNJD-UHFFFAOYSA-L sodium adipate Chemical compound [Na+].[Na+].[O-]C(=O)CCCCC([O-])=O KYKFCSHPTAVNJD-UHFFFAOYSA-L 0.000 description 1
- 239000001601 sodium adipate Substances 0.000 description 1
- 235000011049 sodium adipate Nutrition 0.000 description 1
- 235000012217 sodium aluminium silicate Nutrition 0.000 description 1
- 239000000429 sodium aluminium silicate Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 235000019829 sodium calcium polyphosphate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 235000010226 sodium ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004402 sodium ethyl p-hydroxybenzoate Substances 0.000 description 1
- GTSHREYGKSITGK-UHFFFAOYSA-N sodium ferrocyanide Chemical compound [Na+].[Na+].[Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] GTSHREYGKSITGK-UHFFFAOYSA-N 0.000 description 1
- 235000012247 sodium ferrocyanide Nutrition 0.000 description 1
- 239000000264 sodium ferrocyanide Substances 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 235000019294 sodium fumarate Nutrition 0.000 description 1
- 229940005573 sodium fumarate Drugs 0.000 description 1
- 235000019266 sodium hydrogen malate Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000010268 sodium methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004290 sodium methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 235000010294 sodium orthophenyl phenol Nutrition 0.000 description 1
- 239000004307 sodium orthophenyl phenol Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000019830 sodium polyphosphate Nutrition 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- 235000010230 sodium propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004404 sodium propyl p-hydroxybenzoate Substances 0.000 description 1
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
- 229910052911 sodium silicate Inorganic materials 0.000 description 1
- 235000019794 sodium silicate Nutrition 0.000 description 1
- LROWVYNUWKVTCU-STWYSWDKSA-M sodium sorbate Chemical compound [Na+].C\C=C\C=C\C([O-])=O LROWVYNUWKVTCU-STWYSWDKSA-M 0.000 description 1
- 235000019250 sodium sorbate Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- ODFAPIRLUPAQCQ-UHFFFAOYSA-M sodium stearoyl lactylate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC(C)C(=O)OC(C)C([O-])=O ODFAPIRLUPAQCQ-UHFFFAOYSA-M 0.000 description 1
- 235000010956 sodium stearoyl-2-lactylate Nutrition 0.000 description 1
- 239000003724 sodium stearoyl-2-lactylate Substances 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- UGTZMIPZNRIWHX-UHFFFAOYSA-K sodium trimetaphosphate Chemical compound [Na+].[Na+].[Na+].[O-]P1(=O)OP([O-])(=O)OP([O-])(=O)O1 UGTZMIPZNRIWHX-UHFFFAOYSA-K 0.000 description 1
- 235000019832 sodium triphosphate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- DOJOZCIMYABYPO-UHFFFAOYSA-M sodium;3,4-dihydroxy-4-oxobutanoate Chemical compound [Na+].OC(=O)C(O)CC([O-])=O DOJOZCIMYABYPO-UHFFFAOYSA-M 0.000 description 1
- QYNMSPKSYXPZHG-UHFFFAOYSA-M sodium;4-ethoxycarbonylphenolate Chemical compound [Na+].CCOC(=O)C1=CC=C([O-])C=C1 QYNMSPKSYXPZHG-UHFFFAOYSA-M 0.000 description 1
- PESXGULMKCKJCC-UHFFFAOYSA-M sodium;4-methoxycarbonylphenolate Chemical compound [Na+].COC(=O)C1=CC=C([O-])C=C1 PESXGULMKCKJCC-UHFFFAOYSA-M 0.000 description 1
- IXMINYBUNCWGER-UHFFFAOYSA-M sodium;4-propoxycarbonylphenolate Chemical compound [Na+].CCCOC(=O)C1=CC=C([O-])C=C1 IXMINYBUNCWGER-UHFFFAOYSA-M 0.000 description 1
- WZWGGYFEOBVNLA-UHFFFAOYSA-N sodium;dihydrate Chemical compound O.O.[Na] WZWGGYFEOBVNLA-UHFFFAOYSA-N 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 229950002549 stamulumab Drugs 0.000 description 1
- 239000010676 star anise oil Substances 0.000 description 1
- 235000019430 starch acetate esterified with vinyl acetate Nutrition 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 235000019411 steviol glycoside Nutrition 0.000 description 1
- 229930182488 steviol glycoside Natural products 0.000 description 1
- 150000008144 steviol glycosides Chemical class 0.000 description 1
- 235000019202 steviosides Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000019327 succinylated monoglyceride Nutrition 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 239000001957 sucroglyceride Substances 0.000 description 1
- 235000010964 sucroglyceride Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- UVGUPMLLGBCFEJ-SWTLDUCYSA-N sucrose acetate isobutyrate Chemical compound CC(C)C(=O)O[C@H]1[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O[C@@]1(COC(C)=O)O[C@@H]1[C@H](OC(=O)C(C)C)[C@@H](OC(=O)C(C)C)[C@H](OC(=O)C(C)C)[C@@H](COC(C)=O)O1 UVGUPMLLGBCFEJ-SWTLDUCYSA-N 0.000 description 1
- 235000010983 sucrose acetate isobutyrate Nutrition 0.000 description 1
- 239000001797 sucrose acetate isobutyrate Substances 0.000 description 1
- 235000010965 sucrose esters of fatty acids Nutrition 0.000 description 1
- 239000001959 sucrose esters of fatty acids Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229940044609 sulfur dioxide Drugs 0.000 description 1
- 235000012707 sulphite ammonia caramel Nutrition 0.000 description 1
- 239000004124 sulphite ammonia caramel Substances 0.000 description 1
- 235000010269 sulphur dioxide Nutrition 0.000 description 1
- 235000012751 sunset yellow FCF Nutrition 0.000 description 1
- 239000004173 sunset yellow FCF Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 235000010491 tara gum Nutrition 0.000 description 1
- 239000000213 tara gum Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000001946 tartraric acid esters of mono and diglycerides of fatty acids Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000012756 tartrazine Nutrition 0.000 description 1
- 239000004149 tartrazine Substances 0.000 description 1
- 229960000943 tartrazine Drugs 0.000 description 1
- UJMBCXLDXJUMFB-GLCFPVLVSA-K tartrazine Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-GLCFPVLVSA-K 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 229930006978 terpinene Natural products 0.000 description 1
- 150000003507 terpinene derivatives Chemical class 0.000 description 1
- 229940116411 terpineol Drugs 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010296 thiabendazole Nutrition 0.000 description 1
- 239000004308 thiabendazole Substances 0.000 description 1
- WJCNZQLZVWNLKY-UHFFFAOYSA-N thiabendazole Chemical compound S1C=NC(C=2NC3=CC=CC=C3N=2)=C1 WJCNZQLZVWNLKY-UHFFFAOYSA-N 0.000 description 1
- 229960004546 thiabendazole Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 239000001585 thymus vulgaris Substances 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- 229960003114 tixocortol pivalate Drugs 0.000 description 1
- BISFDZNIUZIKJD-XDANTLIUSA-N tixocortol pivalate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CSC(=O)C(C)(C)C)(O)[C@@]1(C)C[C@@H]2O BISFDZNIUZIKJD-XDANTLIUSA-N 0.000 description 1
- 239000008181 tonicity modifier Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- BJIOGJUNALELMI-UHFFFAOYSA-N trans-isoeugenol Natural products COC1=CC(C=CC)=CC=C1O BJIOGJUNALELMI-UHFFFAOYSA-N 0.000 description 1
- ZCIHMQAPACOQHT-ZGMPDRQDSA-N trans-isorenieratene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/c1c(C)ccc(C)c1C)C=CC=C(/C)C=Cc2c(C)ccc(C)c2C ZCIHMQAPACOQHT-ZGMPDRQDSA-N 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- YWYZEGXAUVWDED-UHFFFAOYSA-N triammonium citrate Chemical compound [NH4+].[NH4+].[NH4+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YWYZEGXAUVWDED-UHFFFAOYSA-N 0.000 description 1
- 239000001393 triammonium citrate Substances 0.000 description 1
- 235000011046 triammonium citrate Nutrition 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 150000003627 tricarboxylic acid derivatives Chemical class 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000015870 tripotassium citrate Nutrition 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 235000019819 trisodium diphosphate Nutrition 0.000 description 1
- YJCJAUSWVUZMSY-UHFFFAOYSA-K trisodium;4-[(2,4-diamino-5-methylphenyl)diazenyl]benzenesulfonate;4-[[2,4-diamino-5-[(4-sulfonatophenyl)diazenyl]phenyl]diazenyl]benzenesulfonate Chemical compound [Na+].[Na+].[Na+].C1=C(N)C(C)=CC(N=NC=2C=CC(=CC=2)S([O-])(=O)=O)=C1N.NC1=CC(N)=C(N=NC=2C=CC(=CC=2)S([O-])(=O)=O)C=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 YJCJAUSWVUZMSY-UHFFFAOYSA-K 0.000 description 1
- SWGJCIMEBVHMTA-UHFFFAOYSA-K trisodium;6-oxido-4-sulfo-5-[(4-sulfonatonaphthalen-1-yl)diazenyl]naphthalene-2-sulfonate Chemical compound [Na+].[Na+].[Na+].C1=CC=C2C(N=NC3=C4C(=CC(=CC4=CC=C3O)S([O-])(=O)=O)S([O-])(=O)=O)=CC=C(S([O-])(=O)=O)C2=C1 SWGJCIMEBVHMTA-UHFFFAOYSA-K 0.000 description 1
- MLIKYFGFHUYZAL-UHFFFAOYSA-K trisodium;hydron;phosphonato phosphate Chemical compound [Na+].[Na+].[Na+].OP([O-])(=O)OP([O-])([O-])=O MLIKYFGFHUYZAL-UHFFFAOYSA-K 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 235000013976 turmeric Nutrition 0.000 description 1
- 229940036248 turpentine Drugs 0.000 description 1
- 208000032471 type 1 spinal muscular atrophy Diseases 0.000 description 1
- 208000032527 type III spinal muscular atrophy Diseases 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 235000012712 vegetable carbon Nutrition 0.000 description 1
- 239000004108 vegetable carbon Substances 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 235000019245 violaxanthin Nutrition 0.000 description 1
- SZCBXWMUOPQSOX-PSXNNQPNSA-N violaxanthin Chemical compound C(\[C@@]12[C@](O1)(C)C[C@H](O)CC2(C)C)=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)/C=C/[C@]1(C(C[C@@H](O)C2)(C)C)[C@]2(C)O1 SZCBXWMUOPQSOX-PSXNNQPNSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 208000021021 weak cry Diseases 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 235000019235 yellow 2G Nutrition 0.000 description 1
- 235000010930 zeaxanthin Nutrition 0.000 description 1
- 239000001775 zeaxanthin Substances 0.000 description 1
- 229940043269 zeaxanthin Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
Definitions
- the present invention relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the treatment of congenital muscular dystrophies, especially Duchenne muscular dystrophy or Becker muscular dystrophy.
- the invention relates in particular to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for said purposes.
- a pharmaceutical combination of 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts and a glucocorticoid for use in these indications is disclosed.
- Pharmaceutical compositions, advantageous formulation techniques and a method of treatment are disclosed.
- CMD Congenital muscular dystrophies
- DMD is an X chromosome-linked recessive progressive wasting disorder caused by a loss of function mutation in the dystrophin gene. Therefore, DMD is nearly exclusively limited to boys. DMD affects approximately 1 in 5,000 male births. Progressive muscle degeneration leads to loss of ambulation at 8 - 12 years of age. Premature death occurs normally between 20 - 30 years due to respiratory and cardiac failure (cf. Guiraud and Davies (2017) Current Opinion in Pharmacology 34: 36-48). Sometimes the life span can be extended with pharmacological treatment into their thirties. Treatment options are still very limited. The most promising approach was a gene therapy in which an intact dystrophin gene should be introduced into the genome. However, it showed only very moderate success, probably due to autoimmune reactions.
- Another approach is exon-skipping.
- antisense oligonucleotides are administered that should skip defect parts of the dystrophin gene thus affording the generation of a version of dystrophin that is still truncated but halfway functional (cf. Dunckley et al. (1998) Human Mol Gen 7: 1083-1090).
- a moderate clinical improvement could be seen in studies with ataluren, while eteplirsen is still under clinical investigation.
- This method requires periodic redelivery into the muscles.
- a systemic delivery route is still under investigation. Therefore, the standard approach is still a pharmacologic symptomatic treatment, trying to slow down the muscular deterioration thus extending the patient’s life span as long as possible.
- the most common prescribed drugs for DMD include glucocorticoids, above all prednisone, prednisolone and deflazacort, as well as 02 agonists such as salbutamol, anticonvulsants to control seizures and immunosuppressants.
- Na + /Ca 2+ exchange pump inhibitors Na + /Ca 2+ exchange pump inhibitors, NF-KB inhibitors, antioxidants, mitochondrial dysfunction modulators, HDAC (histone deacetylase) inhibitors, anti-fibrotic agents, myostatin inhibitors, TGF-0 pathway anti-fibrotic agents and PDE5 inhibitors against muscle ischemia (cf. Guiraud and Davies (2017) Current Opinion in Pharmacology 34: 36-48).
- HDAC histone deacetylase
- glucocorticoids are still the relatively best treatment. However, they entail a huge number of adverse side effects that harshly limit their long-time use. They comprise Cushing’s syndrome, hypertonia, weight gain and obesity (particularly truncal obesity, including the so called “buffalo hump”), edema, puffiness of the face (moon face), potassium loss, muscle weakness, headache, thinning of the skin, easy bruising and slow wound healing, glaucoma, cataracts, stomach and duodenum ulcers, steroid-induced diabetes, loss of control in existing diabetes, osteoporosis (resulting in bone fractures), adrenal joint necrosis (in particular of the hip or the knee joint), psychiatric disturbances (e.g.
- opportunistic infections such as tuberculosis, Herpes zoster and Pneumocystis pneumonia
- reduced effectiveness of antibiotics and vaccines such as tuberculosis, Herpes zoster and Pneumocystis pneumonia
- mice carry a nonsense mutation in the dystrophin gene, thus emulating a similar mutation in human Duchenne muscular dystrophy (and also Becker muscular dystrophy), as can be seen in Examples 1 and 2. It is assumed that the results in this model are predictive not only for DMD but for other congenital muscular dystrophies too.
- 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt leads to a significant improvement in physiologically relevant parameters such as muscle contractile properties and increased body weight, in comparison to control.
- 5-amino-2,3-dihydro-1 ,4-phthalazinedione belongs to the pharmaceutical class of the phthalazinediones. Compounds of this class are known for their beneficial antiinflammatory action.
- 5-amino-2,3-dihydro-1 ,4-phthalazinedione is also known under the name luminol.
- Luminol has excellent chemiluminescent properties. It is widely applied in diagnostic assays as a detection means and in forensic medicine, for example for tracing blood spots. In medicine, 5-amino-2,3-dihydro-1 ,4-phthalazinedione has been developed in the form of a sodium salt.
- acute and chronic inflammatory disorders including a.o. acute infections of bacterial and viral origin, particularly of the intestinal tract, hepatitis B and C, gastroenteritis, inflammations such as prostatitis, endometriosis, throat inflammation, bronchial asthma, pneumonia, periodontitis, pyelonephritis and autoimmune diseases such as Crohn’s disease, ulcerative colitis, lupus erythematosus and scleroderma.
- acute infections of bacterial and viral origin particularly of the intestinal tract, hepatitis B and C
- gastroenteritis inflammations such as prostatitis, endometriosis, throat inflammation, bronchial asthma, pneumonia, periodontitis, pyelonephritis and autoimmune diseases such as Crohn’s disease, ulcerative colitis, lupus erythematosus and scleroderma.
- 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts are well tolerated and have a high safety margin in respect to administered dosages.
- the present application discloses 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of a congenital muscular dystrophy, wherein the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1 ,4- phthalazinedione is 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt.
- 5-amino-2,3-dihydro-1 ,4-phthalazinedione is often used as a hydrate, for example as sodium salt dihydrate.
- the present patent application refers also to the use of all hydrates and other solvates of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts.
- 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts may build complexes with suitable ligands.
- the present patent application refers also to such complexes.
- all hydrates and solvates shall be included in the term “5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts”.
- anhydrous formulations are often preferred.
- Anhydrate forms of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt have been described as crystalline polymorphs in WO 2011/107295 (Form I, Form II) and WO 2016/096143 (Form III). These crystalline polymorphs are virtually free from phase impurities and were characterized by means of X-ray powder diffraction. This method yields a set of characteristic d-values indicating interplanar spacings [A] and of the corresponding 2-theta (20) angles [°] under which Bragg reflections occur. This yields a unique and unambiguous fingerprint of the respective polymorphs.
- Form II is characterized by the following values: d values: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and/or
- Form III yielded the following values: d values: 13.131 ; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288; 3.283;
- 5-amino-2,3-dihydro-1,4-phthalazinedione itself shows also polymorphism.
- a Form I (Paradies (1992) Ber. Bunsen-Ges. Phys. Chem 96: 1027-1031) and a Form II (WO 2017/140430) have been disclosed.
- the present patent application refers also to the use according to the disclosure of all crystalline forms and polymorphs thereof of 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts.
- the use of Form II of 5-amino-2,3-dihydro-1,4- phthalazinedione is preferred.
- phthalazinediones Similar therapeutic effects are known for a variety of phthalazinediones, respectively of derivatives of 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts.
- An example is 6-amino-2,3-dihydrophthalazine-1, 4-dione (isoluminol).
- An overview of suitable phthalazinediones is given in WO 2007/018546. It is reasonable to assume that these compounds show comparable effects when being used for the therapeutic applications according to the disclosure.
- Tautomerism relates to a rapid intraconversion of organic compounds in which a hydrogen atom or proton formally migrates inside the compound. This is accompanied by a switch of a single bond and adjacent double bond.
- the single forms are called tautomers.
- keto-enol tautomerism occurs in 5-amino-2,3-dihydro-1,4-phthalazinedione (Proescher and Moody (1939) J Lab Clin Med, 1183-1189).
- the present patent application refers also to the use of all tautomers of 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts.
- 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts shall encompass all beforementioned molecular variants of 5-amino-2,3-dihydro-1 ,4-phthalazinedione, i.e., 5- amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts or solvates, hydrates, crystalline polymorphs or tautomers thereof.
- excipient is used in this application to describe any component of a pharmaceutical composition apart of the pharmaceutically active principle. The selection of suitable excipients depends on a variety of factors, such as the dosage form, the dosage, the desired solubility and the stability of the composition.
- effect refers to causally occurring beneficial consequences in the organism to which said substance has been administered before.
- the terms “effective amount” and “therapeutically effective amount” refer to an amount of the substance of the invention that is sufficiently large to cause a desired beneficial effect in a subject in need of such a treatment.
- treatment and “therapy” comprise the administration of at least the substance of the invention, alone or in combination with at least one further pharmaceutical drug, independently of the chronological order of the administration.
- Such an administration is intended to substantially improve the disease course of a congenital muscular dystrophy by stopping or decelerating the increase of disabilities during the course of the disease.
- prophylaxis or “prophylactic treatment” comprise the administration of at least the substance of the invention, alone or in combination with at least one further pharmaceutical drug, independently of the chronological order of the administration, in order to prevent or suppress the manifestation of symptoms attributed to a congenital muscular dystrophy. It refers in particular to medical conditions of a patient in which the manifestation of such symptoms is expected to occur in the far or near future with a reasonable probability.
- subject and “patient” comprise individuals suffering from disease symptoms or disabilities related to a congenital muscular dystrophy wherein said diagnosis is either approved or suspected.
- Individuals are mammals, in particular humans.
- muscle dystrophies is not always precisely used in scientific and popular literature. Sometimes it refers also to general conditions of a wasting of muscle mass or massive weight loss, as e.g., sarcopenia, cachexia after cancer, chemotherapy or excessive fasting, dexamethasone-induced muscle wasting or age-related muscle wasting (for example in Sakuma et al. (2014) Front Aging Neurosci G 230; Saimithra et al. (2016) http://nopr.niscpr.res.in/handle/123456789/44283 ). These conditions should be better termed “muscle atrophies”.
- the present disclosure relates only to muscular dystrophies in a stricter sense. To avoid any ambiguities, the term “congenital muscular dystrophies” is used throughout the present disclosure.
- CMD Congenital muscular dystrophies
- CMD Congenital muscular dystrophies
- CMD become manifest with progressive muscle weakness, muscle atrophy, spasm, muscle hypertonia, and myalgias.
- Many CMD involve cardiac failure and respiratory dysfunction, leading to premature death.
- Over 800 monogenic mutations have been associated with human CMD. Most of them are associated with genes encoding for structural muscle proteins (Chemello et al. (2020) J Clin Invest 130: 2766-2776).
- Duchenne muscular dystrophy is the most common muscular hereditary disease. Prevalence ranges from 1 :3,600 to 1 :6,000. Because of the X-linked recessive inheritance nearly exclusively boys are affected. The onset of muscle weakness starts around the age of four. Disease progression is quick. Muscle loss typically occurs first in the thighs and pelvis followed by the arms. Most are unable to walk by the age of 12. Due to muscle wasting a painful malposition of the articulations and bone deformation occur. With adequate disease management patients can reach their fourth decade. At a late stage severe cardiovascular and respiratory problems will finally lead to death.
- DMD Duchenne muscular dystrophy
- the disease is caused by a mutation in the gene for the protein dystrophin.
- Dystrophin is important to maintain the muscle fiber's cell membrane by linking the cell membrane with the actin filaments of the cytoskeleton.
- Cellular pathophysiology includes mitochondrial dysfunction, reduced ATP levels and an increased Ca 2+ influx due to the damaged sarcolemma. Damaged mitochondria are not able anymore to buffer intracellular Ca 2+ surges.
- pAMPK phosphorylated AMP-activated protein kinase
- nNOS neurovascular NO synthase
- glucocorticoids Prednisone, prednisolone and deflazacort are commonly prescribed.
- the new synthetic glucocorticoid vamorolone is still under development for DMD.
- the objective is to retard muscle degeneration.
- P2 agonists such as salbutamol are used as well as anticonvulsants to control seizures and immunosuppressants.
- Na7Ca 2+ exchange pump inhibitors NF-KB inhibitors
- antioxidants mitochondrial dysfunction modulators
- HDAC histone deacetylase
- anti-fibrotic agents myostatin inhibitors
- TGF-0 pathway anti-fibrotic agents PDE5 inhibitors against muscle ischemia
- a CMD similar to DMD is Becker muscular dystrophy (BMD; synonym: Becker-Kiener muscular dystrophy). It is likewise an inherited disorder of the dystrophin gene. The associated point mutation in the dystrophin gene affords for the generation of a truncated protein, but in contrast to DMD, this truncated dystrophin is still partially working. Therefore, the disease course is milder than in DMD. Patients can often still maintain an active lifestyle. The prevalence of BMD is approximately 1.5 to 6 in 100,000 male births and thus less frequent than DMD. Symptoms usually appear around ages 8 to 25. In unfortunate disease courses patients may die at age of 40, others reach a normal age.
- Symptoms include typically progressive muscle weakness of the legs and the pelvis, leading to a gradual difficulty with walking. Further symptoms are upper extremity muscle weakness, toe-walking, breathing difficulties, skeletal deformities such as scoliosis, pseudohypertrophy of calf muscles, muscle cramps, heart muscle problems and elevated creatine kinase levels in blood (htpps://patient.info/doctor/beckers-muscular dystrophy, as of September 12 th , 2021). There is no known cure for BMD. Physical therapy may help to mitigate the symptoms. The glucocorticoid prednisone is administered for increasing the production of the dystrophin- related protein utrophin. Because of the comparable etiology the same medications are used as in DMD.
- the group of limb girdle dystrophies are associated with point mutations in the autosomally located genes encoding for a-, -, y-, 8- and e-sarcoglycanes.
- Sarcoglycanes are transmembrane proteins involved in the protein complex responsible for connecting the muscle fiber skeleton to the extracellular matrix.
- the age of onset us usually 10 to 30 years of age. Both genders are affected equally. Prevalence is about 1 : 14,500.
- a progressive muscle wasting occurs that affects predominantly hip and shoulder muscles. Symptoms include great difficulties in walking, bending over and squatting, Further symptoms are pseudohypertrophy, muscle hypertrophy, respiratory muscle problems, palpitation, distal muscle problems, facial muscle weakness and weak shoulder muscles. Normally, limb girdle dystrophies do not have a fatal course. Physical therapy may help to alleviate the symptoms. Until now there is no pharmaceutical therapy. However, antioxidant therapy is suggested.
- dysferlinopathies encompasses myopathies caused by a mutation in the gene DYSF which encodes for dysferlin, a protein linked with skeletal muscle repair.
- Examples for dysferlinopathies include Miyoshi myopathy, limb girdle muscular dystrophy type 2B and distal myopathy. These diseases become usually apparent in the third of fourth decade of life. Typical symptoms are weakness and wasting of voluntary skeletal muscles such as the gastrocnemius muscle and the anterior tibial muscles. A focus of prevalence is the Middle East and the Indian subcontinent. Until now, no curative treatment exists.
- IV-IG intravascular immunoglobulins
- GNE bifunctional UDP-/V-acetylglucosamine 2-epimerase / N- acetylmannosamine kinase myopathies includes hereditary inclusion body myopathy (HIBM), distal myopathy with rimmed vacuoles (DMRV), Nonaka distal myopathy and quadriceps-sparing myopathy. These mutations are most frequent in persons of Egyptian Jewish descent. Muscle wasting starts around the age of 20 to 30 years, with a disease course of 10 to 15 years to disability. Symptoms include difficulty in walking on heels and in running, a weak index finger, frequent loss of balance. Until now, there is only palliative treatment, e.g. with ankle foot orthoses.
- SMA spinal and bulbar muscular atrophies
- SMARD1 Werdnig- Hoffmann disease and Kugelberg-Welander disease. These disorders are characterized by a degeneration of motoneurons in the anterior horn. This is due to a mutation in the SMN1 gene that encodes for the so-called survival of motoneuron protein. It is inherited in an autosomal recessive manner. Symptoms include areflexia, particularly in the extremities, general muscle weakness, poor muscle tone, difficulties in sitting, standing and walking, weak cough and weak cry in infants, a bell-shaped torso, fasciculation of the tongue and sucking and swallowing difficulties.
- nusinersen an antisense nucleotide that modifies the alternative splicing of the adjuvant SMN2 gene
- transgenic treatment with onahimogene as well as risdiplam
- a pyridazine derivative that also modifies the SMN2 splicing pattern. If left untreated, most infant patients do not reach the age of 4. This disease is the major course of infant death due to a genetic cause. As there is no adequate pharmaceutical treatment, SMA patients tend to deteriorate over time.
- the pathophysiology includes oxidative stress.
- the curcumin derivative ASC-JM17, a Nrf2 activator showed to be beneficial.
- Myotonic dystrophy is an autosomal hereditary disease that causes progressive muscle loss and wasting. Muscles are often unable to relax after contraction. Other common symptoms are cataracts, intellectual disability and heart conduction problems Prevalence is about 1 :8,000 worldwide. The age of onset is typically in the 20s and 30s. The disease is caused by a mutation in the DMPK gene encoding for myotonin-protein kinase (type 1 , DM1) or by a mutation is the CNBP gene encoding for cellular nuclear acid-binding protein (type 2, DM2). Currently, there is no cure for the disease. Treatments include braces or wheelchairs, pacemakers and non-invasive positive pressure ventilation. Mexiletine or carbamazepine are prescribed for muscle relaxation. Pain may be treated with tricyclic antidepressants and NSAIDs (non-steroidal anti-inflammatory drugs) (cf. Meola and Cardani (2015) Biochim Biophys Acta 1852: 594-606).
- NSAIDs non-ster
- Emery-Dreyfuss muscular dystrophy is caused by a mutation in the gene encoding for emerin.
- EDMD1 - EDMD7 There are types EDMD1 - EDMD7. Symptoms include muscle weakness, above all in the shoulders and lower legs, shortening of the Achilles tendon and the elbow muscles, bradycardia, palpitations, contractures of the muscles. In the course of the disease patients may need orthopedics (walker, cane), physical therapy and respiratory aid. Pharmaceutical treatment is based on beta-blockers and ACE inhibitors.
- Facioscapulohumeral muscular dystrophy is caused by a mutation leading to a dysregulation of the gene encoding for double homeobox 4 (DUX4).
- DUX4 double homeobox 4
- Prevalence ranges between 1 :8,000 and 1 :20,000.
- the disease typically becomes manifest between 15 and 30 years of age. Life expectancy is normally not reduced. No therapy could considerably slow down the progress of the disease until now. Treatment includes physical and occupational therapy as well as reconstructive surgery, if needed.
- compositions focuses on the glucocorticoid prednisone, the [32 agonist albuterol, the calcium channel blocker diltiazem, stamulumab (an antibody inhibiting myostatin) and the TGF-p inhibitor ACE-083.
- Oculopharyngeal muscular dystrophy is characterized by an autosomal mutation in the gene encoding for polyadenylate-binding protein 2 (PABPN1). The onset is relatively late in life (40 - 50 years of age). Symptoms include ptosis, weakness of extraocular muscles, dysphagia, aspiration pneumonia and proximal limb weakness. Currently, no therapy exists for stopping disease progress. Treatment attempts target specific diets and cricopharyngeal myotomy to mitigate the symptoms.
- PABPN1 polyadenylate-binding protein 2
- Myofibrillar myopathies are a group of clinically and genetically heterogeneous diseases of the skeletal musculature with an age of onset after 40 years of age. Clinically, slowly progressive muscle weakness with varying distribution of pareses is typical; a differentiation is made between distal, scapuloperoneal, and limb-girdle phenotypes, potentially accompanied by cardiomyopathy, pulmonary involvement, and peripheral neuropathy. Morphology reveals dissolution of myofibrils, deposition of myofibrillar degradation products, abnormal expression of numerous intramuscular proteins, and intracellular desmin-positive protein aggregates.
- Affected genes are DES (desmin), MYOT (myotilin), LDB3 (LIM-domain binding 3, ZASP), FLNC (filamin C), CRYAB (alpha-crystalline B), BAG3 (BAG family molecular chaperone regulator 3), FHL1 (four and a half LIM domain protein 1) and DNAJB6 (DNaJ homolog subfamily B member 6).
- DES desmin
- MYOT myotilin
- LDB3 LIM-domain binding 3, ZASP
- FLNC filament C
- CRYAB alpha-crystalline B
- BAG3 BAG family molecular chaperone regulator 3
- FHL1 four and a half LIM domain protein 1
- DNAJB6 DNaJ homolog subfamily B member 6
- the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscular dystrophy or Becker muscular dystrophy.
- the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscular dystrophy or Becker muscular dystrophy.
- the present application refers to 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of a congenital muscular dystrophy that is selected from a group consisting of limb girdle dystrophies, dysferlinopathies, GNE myopathies, spinal and bulbar muscular atrophies, myotonic dystrophy, Emery-Dreyfuss muscular dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, myofibrillar myopathies, Walker-Warburg syndrome, lamin A/C-related congenital muscular dystrophy, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy with partial merosin deficiency, rigid spine muscular dystrophy, congenital muscular dystrophy with primary laminin 2 deficiency, LARGE-related congenital muscular dystrophy, muscle-eye-brain
- the present application refers thus also to a pharmaceutical composition consisting of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy.
- the present application refers thus to a pharmaceutical composition consisting of 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt and at least one glucocorticoid for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy.
- the present application refers to a pharmaceutical composition consisting of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid for use in the treatment of a congenital muscular dystrophy that is selected from a group consisting of limb girdle dystrophies, dysferlinopathies, GNE myopathies, spinal and bulbar muscular atrophies, myotonic dystrophy, Emery-Dreyfuss muscular dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, myofibrillar myopathies, Walker-Warburg syndrome, lamin A/C-related congenital muscular dystrophy, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy with partial merosin deficiency, rigid spine muscular dystrophy, congenital muscular dystrophy with primary laminin 2 deficiency
- glucocorticoids selected from a group comprising prednisone, prednisolone, deflazacort, vamorolone, flumethasone, triamcinolone acetonide, betamethasone, dexamethasone, beclomethasone, betamethasone valerate, betamethasone dipropionate, budesonide, beclomethasone dipropionate, isoflupredone, fluocinonide, fluocinolone, methylprednisolone, halcinonide, desonide, deltasone, triamcinolone, triamcinolone acetonide, tixocortol pivalate, mometasone furoate, amcinonide, fluocortolone, halometasone, alclometasone dipropionate, prednicarbate, clobetasone-17- butyrate, clobetasol-17-propionate, prednicarbat
- the present application refers to a pharmaceutical composition containing 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts or the pharmaceutical combination as defined before and at least one pharmaceutically acceptable excipient for use in the treatment of congenital muscular dystrophies.
- this pharmaceutical composition for use in the treatment of Duchenne muscular dystrophy or Becker muscular dystrophy.
- pharmaceutically acceptable excipient(s) refers to natural or synthetic compounds that are added to a pharmaceutical formulation alongside the pharmaceutical active agent. They may help to bulk up the formulation, to enhance the desired pharmacokinetic properties or the stability of the formulation, as well as being beneficial in the manufacturing process.
- compositions include, carriers, binding agents, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickening agents, pH-regulators, acidity regulators, acidifiers, solvents, isotonizing agents, disintegrants, glidants, lubricants, emulsifiers, solubilizing agents, stabilizers, diluents, anticaking agents (antiadherents), sorbents, permeation enhancers, foaming agents, antifoaming agents, opacifiers, fatliquors, consistency enhancers, hydrotropes, aromatic and flavoring substances.
- one or more pharmaceutically acceptable carriers are added to a pharmaceutically active agent.
- Eligible are all carriers known in the art and combinations thereof.
- solid dosage forms they can be for example plant and animal fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talcum, zinc oxide.
- suitable carriers are for example solvents, solubilizing agents, emulsifiers such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butyl glycol, cotton seed oil, peanut oil, olive oil, castor oil, sesame oil, glycerol fatty acid esters, polyethylglycols, fatty acid esters of sorbitan.
- solvents such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butyl glycol, cotton seed oil, peanut oil, olive oil, castor oil, sesame oil, glycerol fatty acid esters, polyethylglycols, fatty acid esters of sorbitan.
- Suspensions according to the disclosure may use carriers known in the art such as diluents (e.g., water, ethanol or propylene glycol), ethoxylated isostearyl alcohols, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonites, agar agar, tragacanth.
- diluents e.g., water, ethanol or propylene glycol
- ethoxylated isostearyl alcohols ethoxylated isostearyl alcohols
- polyoxyethylene and polyoxyethylene sorbitan esters e.g., polyoxyethylene and polyoxyethylene sorbitan esters
- microcrystalline cellulose e.g., bentonites, agar agar, tragacanth.
- binding agents refers to substances that bind powders or glue them together, rendering them cohesive through granule formation. They serve as a “glue” of the formulation. Binding agents increase the cohesive strength of the provided diluent or filler.
- Suitable binding agents are for example starch from wheat, corn, rice or potato, gelatin, naturally occurring sugars such as glucose, sucrose or beta-lactose, sweeteners from corn, natural and synthetic gums such as acacia, tragacanth or ammonium calcium alginate, sodium alginate, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, magnesium aluminum silicate, waxes and others.
- the percentage of the binding agent in the composition can range from 1 - 30 % by weight, preferred 2 - 20 % by weight, more preferred 3 - 10 % by weight and most preferred 3 - 6 % by weight.
- Colorants are excipients that bestow a colorization to the pharmaceutical formulation. These excipients can be food colorants. They can be adsorbed on a suitable adsorption means such as clay or aluminum oxide. A further advantage of a colorant is that it may visualize spilled aqueous solution on the nebulizer and/or the mouthpiece to facilitate cleaning.
- the amount of the colorant may vary between 0.01 and 10 % per weight of the pharmaceutical composition, preferred between 0.05 and 6 % per weight, more preferred between 0.1 and 4 % per weight, most preferred between 0.1 and 1 % per weight.
- Suitable pharmaceutical colorants are for example curcumin, riboflavin, riboflavin-5’- phosphate, tartrazine, alkannin, quinolione yellow WS, Fast Yellow AB, riboflavin-5’-sodium phosphate, yellow 2G, Sunset yellow FCF, orange GGN, cochineal, carminic acid, citrus red 2, carmoisine, amaranth, Ponceau 4R, Ponceau SX, Ponceau 6R, erythrosine, red 2G, Allura red AC, Indanthrene blue RS, Patent blue V, indigo carmine, Brilliant blue FCF, chlorophylls and chlorophyllins, copper complexes of chlorophylls and chlorophyllins, Green S, Fast Green FCF, Plain caramel, Caustic sulphite caramel, ammonia caramel, sulphite ammonia caramel, Black PN, Carbon black, vegetable carbon, Brown FK, Brown HT, alpha-carotene, beta
- buffer solutions are preferred for liquid formulations, in particular for pharmaceutical liquid formulations.
- the terms buffer, buffer system and buffer solution, in particular of an aqueous solution, refer to the capacity of the system to resist a pH change by the addition of an acid or a base, or by dilution with a solvent.
- Preferred buffer systems may be selected from the group comprising formate, lactate, benzoic acid, oxalate, fumarate, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinate, pyridine, phthalate, histidine, MES (2-(/V-morpholino) ethanesulfonic acid), maleic acid, cacodylate (dimethyl arsenate), carbonic acid, ADA (/V-(2-acetamido)imino diacetic acid, PIPES (4- piperazine-bis-ethanesulfonic acid), BIS-TRIS propane (1,3- bis[tris(hydroxymethyl)methylamino] propane), ethylene diamine, ACES (2-[(amino-2- oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3-(/V-morpholino) propanesulfonic acid), diethyl malonic acid, TES (2-
- carbonic acid buffers such as acetate buffer and dicarboxylic acid buffers such as fumarate, tartrate and phthalate as well as tricarboxylic acid buffers such as citrate.
- a further group of preferred buffers are inorganic buffers such as sulfate hydroxide, borate hydroxide, carbonate hydroxide, oxalate hydroxide, calcium hydroxide and phosphate buffers.
- inorganic buffers such as sulfate hydroxide, borate hydroxide, carbonate hydroxide, oxalate hydroxide, calcium hydroxide and phosphate buffers.
- nitrogen-containing puffers such as imidazole, diethylene diamine and piperazine.
- sulfonic acid buffers such as TES, HEPES, ACES, PIPES, [(2-hydroxy-1 ,1-bis-(hydroxymethyl)ethyl)amino]-1- propanesulfonic acid (TAPS), 4-(2-hydroxyethyl)piperazine-1 -propanesulfonic acid (EEPS), MOPS and A/,A/-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES).
- TAPS 2-hydroxy-1 ,1-bis-(hydroxymethyl)ethyl)amino]-1- propanesulfonic acid
- EEPS 4-(2-hydroxyethyl)piperazine-1 -propanesulfonic acid
- MOPS A/,A/-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid
- Another group of preferred buffers are glycine, glycyl-glycine, glycyl-glycyl-glycine, A/,/V-bis-(2- hydroxyethyl)glycine and A/-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricine).
- amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxy proline, N,N,N- trimethyllysine, 3-methyl histidine, 5-hydroxy lysine, o-phosphoserine, gammacarboxyglutamate, [epsilon]-/V-acetyl lysine, [omega]-/V-methyl arginine, citrulline, ornithine and their derivatives.
- KH2PO4 buffer Particularly preferred is KH2PO4 buffer.
- Preservatives for liquid and/or solid dosage forms can be used on demand. They may be selected from the group comprising, but not limited to, sorbic acid, potassium sorbate, sodium sorbate, calcium sorbate, methyl paraben, ethyl paraben, methyl ethyl paraben, propyl paraben, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, heptyl p-hydroxybenzoate, sodium methyl para-hydroxybenzoate, sodium ethyl parahydroxybenzoate, sodium propyl para-hydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohols, cresols, cetylpyridinium chloride, chlorobutanol, thiomersal (sodium 2-(ethylmercurithio) benzoic acid), sulfur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, potassium
- antioxidants include sodium metabisulfite, alphatocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisol, butylated hydroxytoluene, fumaric acid or propyl gallate. Preferred is the use of sodium metabisulfite, alpha-tocopherol and ascorbyl palmitate.
- Tablets or pills are usually coated i.e., the coating constitutes the outer layer.
- This can be a film coating, a sugar coating with saccharides and a compression coating.
- Pharmaceutically acceptable varnishes or waxes, HPMC (hydroxypropylmethylcellulose), MC (methylcellulose) or HPC (hydroxypropylcellulose) can be used.
- Such a coating may help to disguise the taste, to ease the swallowing or the identification.
- plasticizers and pigments are included in the coating.
- Capsules normally have a gelatinous envelope that encloses the active substance(s). The specific composition and thickness of this gelatinous layer determines how fast absorption takes place after ingestion of the capsule. Of special interest are sustained release formulations, as known in the art.
- Suitable sweeteners can be selected from the group comprising mannitol, glycerol, acesulfame potassium, aspartame, cyclamate, isomalt, isomaltitol, saccharin and its sodium, potassium and calcium salts, sucralose, alitame, thaumatin, glycyrrhizin, neohesperidine dihydrochalcone, steviol glycosides, neotame, aspartame-acesulfame salt, maltitol, maltitol syrup, lactitol, xylitol, erythritol.
- Suitable thickening agents can be selected from the group comprising, but not limited to, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, dextrins, polydextrose, modified starch, alkaline modified starch, bleached starch, oxidized starch, enzyme-treated starch, monostarch phosphate, distarch phosphate esterified with sodium trimetaphosphate or phosphorus oxychloride, phosphate distarch phosphate, acetylated distarch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated distarch adipate, acetylated distarch glycerol, distarch glycerin, hydroxypropyl starch, hydroxy propyl distarch glycerin, hydroxypropyl distarch phosphate,
- Suitable pH-regulators for liquid dosage forms are e.g., sodium hydroxide, hydrochloric acid, buffer substances such as sodium dihydrogen phosphate or disodium hydrogenphosphate.
- Suitable acidity regulators can be selected from the group comprising acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, carbon dioxide, malic acid, fumaric acid, sodium lactate, potassium lactate, calcium lactate, ammonium lactate, magnesium lactate, citric acid, mono-, di-, trisodium citrate, mono-, di-, tripotassium citrate, mono-, di-, tricalcium citrate, tartaric acid, mono-, disodium tartrate, mono-, dipotassium tartrate, sodium potassium tartrate, ortho-phosphoric acid, lecithin citrate, magnesium citrate, ammonium malate, sodium malate, sodium hydrogen malate, calcium malate, calcium hydrogen malate, adipic acid, sodium adipate, potassium adipate, ammonium adipate, succinic acid, sodium fumarate, potassium fumarate, calcium fumarate, ammonium fumarate, 1 ,4-heptonolactone, triammonium
- Suitable solvents may be selected from the group comprising, but not limited to, water, carbonated water, water for injection, water with isotonizing agents, saline, isotonic saline, alcohols, particularly ethyl and n-butyl alcohol, and mixtures thereof.
- Suitable isotonizing agents are for example pharmaceutically acceptable salts, in particular sodium chloride and potassium chloride, sugars such as glucose or lactose, sugar alcohols such as mannitol and sorbitol, citrate, phosphate, borate and mixtures thereof,
- Suitable disintegrants can be selected from the group comprising starch, cold water-soluble starches such as carboxymethyl starch, cellulose derivatives such as methyl cellulose and sodium carboxymethyl cellulose, microcrystalline cellulose and cross-linked microcrystalline celluloses such as croscarmellose sodium, natural and synthetic gums such as guar, agar, karaya (Indian tragacanth), locust bean gum, tragacanth, clays such as bentonite, xanthan gum, alginates such as alginic acid and sodium alginate, foaming compositions a.o.
- starch cold water-soluble starches
- cellulose derivatives such as methyl cellulose and sodium carboxymethyl cellulose
- microcrystalline cellulose and cross-linked microcrystalline celluloses such as croscarmellose sodium
- natural and synthetic gums such as guar, agar, karaya (Indian tragacanth), locust bean gum, tragacanth
- clays such as bentonit
- Moisture expansion is supported by for example starch, cellulose derivatives, alginates, polysaccharides, dextrans, cross-linked polyvinyl pyrrolidone.
- the amount of the disintegrant in the composition may vary between 1 and 40% per weight, preferred between 3 and 20% per weight, most preferred between 5 and 10% per weight.
- Glidants are materials that prevent a baking of the respective supplements and improve the flow characteristics of granulations so that the flow is smooth and constant.
- Suitable glidants comprise silicon dioxide, magnesium stearate, sodium stearate, starch and talcum.
- the amount of the glidant in the composition may vary between 0.01 and 10% per weight, preferred between 0.1 and 7% per weight, more preferred between 0.2 and 5% per weight, most preferred between 0.5 and 2% per weight.
- Lubricants refers to substances that are added to the dosage form in order to facilitate tablets, granulates etc. to be released from the press mold or the outlet nozzle. They diminish friction or abrasion. Lubricants are usually added shortly before pressing, as they should be present on the surface of the granules and between them and the parts of the press mold.
- the amount of the lubricant in the composition may vary between 0.05 and 15% per weight, preferred between 0.2 and 5% per weight, more preferred between 0.3 and 3% per weight, most preferred between 0.3 and 1.5% per weight. Suitable lubricants are a.o.
- sodium oleate metal stearates such as sodium stearate, calcium stearate, potassium stearate and magnesium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, boric acid, waxes having a high melting point, polyethylene glycol.
- Emulsifiers can be selected for example from the following anionic and non-ionic emulsifiers: Anionic emulsifier waxes, cetyl alcohol, cetylstearyl alcohol, stearic acid, oleic acid, polyoxyethylene polyoxypropylene block polymers, addition products of 2 to 60 mol ethylene oxide to castor oil and/or hardened castor oil, wool wax oil (lanolin), sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethene sorbitan monolaurate, polyoxyethene sorbitan monooleate, polyoxyethene sorbitan monopalmitate, polyoxyethene sorbitan monostearate, polyoxyethene sorbitan tristearate, polyoxyethene stearate, polyvinyl alcohol, metatartaric acid, calcium tartrate, alginic acid, sodium alginate, potassium alginate, am
- glycerin monooleate stearic acid
- phospholipids such as lecithin.
- Suitable as surface-active solubilizing agents are for example diethylene glycol monoethyl ester, polyethyl propylene glycol co-polymers, cyclodextrins such as a- and p- cyclodextrin, glyceryl monostearates such as Solutol HS 15 (Macrogol-15-hydroxystearate from BASF, PEG 660-15 hydroxystearates), sorbitan esters, polyoxyethylene glycol, polyoxyethylene sorbitanic acid esters, polyoxyethylene sorbitan monooleate, polyoxyethylene oxystearic acid triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, (anionic) glyceryl monooleates.
- solubilizers are for example diethylene glycol monoethyl ester, polyethyl prop
- Stabilizers are substances that can be added to prevent unwanted changes. Though stabilizers are not real emulsifiers they may also contribute to the stability of emulsions. Suitable examples for stabilizers are oxystearin, xanthan gum, agar, oat gum, guar gum, tara gum, polyoxyethene stearate, aspartame-acesulfame salt, amylase, proteases, papain, bromelain, ficin, invertase, polydextrose, polyvinyl pyrrolidone, polyvinyl polypyrrolidone, triethyl citrate, maltitol, maltitol syrup.
- Diluents or fillers are inactive substances added to drugs for handling minimal amounts of active agents.
- suitable diluents are water, mannitol, pre-gelatinized starch, starch, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate dihydrate, calcium phosphate, calcium carbonate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, xanthan gum, gum arabic or any combination thereof.
- Anti-caking agents can be added to a supplement or a composition of supplements for preventing the formation of lumps and for easing packaging, transport, release from the at least one chamber of the dispensing cap and consumption.
- Suitable examples include tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethyl siloxane.
- Sorbents are materials that soak up oil from the water. Suitable examples include natural sorbents such as peat moss, sawdust, feathers, and anything else natural that contains carbon and synthetic sorbents such as polyethylene and nylon. Sorbents are used for tablet/capsule moisture-proofing by limited fluid sorbing (taking up of a liquid or a gas either by adsorption or by adsorption) in a dry state.
- Permeation enhancers are often used in topical dosage forms. Suitable permeation enhancers comprise all pharmaceutically acceptable permeation enhancers known in the art, such as, without being limiting, azones such as laurocapram, 1-dodecylazacycloheptan-2-one; sulfoxides such as dimethyl sulfoxide, DMAC, DMF; pyrrolidones such as 2-pyrrolidone, N- methyl-2-pyrrolidone; alcohols such as ethanol, 1 ,2-propandiol or decanol; glycols such as propylene glycol, diethylene glycol, tetraethylene glycol; fatty acids such as oleic acid, lauric acid, sodium lauryl sulfate, myristic acid, isopropyl myristic acid, capric acid; nonic surfactants such as polyoxyethylene-2-oleyl ether, polyoxyethylene-2-stearyl ether; terpenes; terpen
- citric acid esters such as triethyl citrate; hydrophobin polypeptides; alpha-bisabolol; dimethyl isosorbide (Arlasove® DMI); ethoxydiglycol. Preferred is 1 ,2-propandiol.
- a liquid oral dosage form generates some foam on being dissolved.
- Such an effect can be supported through the addition of a foaming agent that reduces the surface tension of the liquid, thus facilitating the formation of bubbles, or it increases its colloidal stability by inhibiting coalescence of bubbles.
- foam it may stabilize foam.
- suitable examples include mineral oil, quillaia extract, triethyl citrate, sodium lauryl ether sulfate, sodium lauryl sulfate, ammonium lauryl sulfate.
- liquid oral dosage forms may appear slightly foamy upon preparation. Though this does not interfere with the desired application it may affect patient compliance in case of a medication or the commercial success in case of dietary supplements. Therefore, it may be desirable to add a pharmaceutically acceptable anti-foaming agent (defoamer).
- a pharmaceutically acceptable anti-foaming agent defoamer
- examples are polydimethylsiloxane or silicone oil in dietary supplements or simethicone in pharmaceuticals.
- Opacifiers are substances that render the liquid dosage for, opaque, if desired. They must have a refractive index substantially different from the solvent, in most cases here water. At the same time, they should be inert to the other components of the composition. Suitable examples include titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof.
- Suitable fatliquors are e.g., oleic acid decyl ester, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, sodium laurylsulfate.
- Consistency enhancers are e.g., cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline waxes, non-ionic emulsifier waxes, beeswax, paraffin or stearyl alcohol.
- Suitable hydrotropes are alcohols such as ethanol, isopropyl alcohol or polyols such as glycerin.
- Suitable aromatic and flavoring substances comprise above all essential oils that can be used for this purpose. In general, this term refers to volatile extracts from plants or parts of plants with the respective characteristic smell. They can be extracted from plants or parts of plants by steam distillation.
- Essential oils respectively aromatic substances from achillea, sage, cedar, clove, chamomile, anise, aniseed, star anise, thyme, tea tree, peppermint, mint oil, menthol, cineol, borneol, zingerol, eucalyptus, mango, figs, lavender oil, chamomile blossoms, pine needle, cypress, orange, rose, rosewood, plum, currant, cherry, birch leaves, cinnamon, lime, grapefruit, tangerine, juniper, valerian, lemon, lemon balm, lemon grass, palmarosa, cranberry, pomegranate, rosemary, ginger, pineapple, guava, echinacea, ivy leave extract, blueberry, kaki, melon, alpha- or beta-pinene, alpha-pinene oxide, alpha- campholenic aldehyde, alpha-citronellol, alpha-isoa
- aromatic or flavoring substances can be included in the range of 0.0001 to 10 % per weight (particularly in a composition), preferred 0.001 to 6% per weight, more preferred 0.001 to 4% per weight, most preferred 0.01 to 1% per weight, with regard to the total composition.
- Application- or single case-related it may be advantageous to use differing quantities.
- the present application relates to 5-amino-2,3-dihydro-1,4- phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for use in a formulation for oral administration in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy.
- compositions suitable for oral dosage forms of 5-amino-2,3-dihydro-1,4- phthalazinedione or one of its pharmaceutically acceptable salts may be administered as separate units such as tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills; powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or in oil-in-water or water-in-oil in emulsions.
- the active agent in oral dosage forms such as tablets or capsules can thus be combined with a non-toxic and pharmaceutically acceptable inert carrier such as ethanol, glycerol or water.
- a non-toxic and pharmaceutically acceptable inert carrier such as ethanol, glycerol or water.
- Powders are produced by grinding the compound to a suitably tiny particle size and mixing them with a pharmaceutical carrier in a similar manner e.g., an edible carbohydrate such as starch or mannitol.
- a flavor, preservative, dispersant or colorant can also be present.
- Tablets are formulated by producing, granulating or dry pressing a powder mixture, adding a lubricant and a disintegrants and pressing the mixture to a tablet.
- a powder mixture is produced by mixing a suitably ground compound with a diluent or a base as described before, and if applicable, with a binding agent such as carboxymethyl cellulose, an alginate, gelatin or polyvinyl pyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbent, such as, for example, bentonite, kaolin or dicalcium phosphate.
- a binding agent such as carboxymethyl cellulose, an alginate, gelatin or polyvinyl pyrrolidone
- a dissolution retardant such as, for example, paraffin
- an absorption accelerator such as, for example, a quaternary salt
- an absorbent such as, for example, benton
- the powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acacia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve.
- a binder such as, for example, syrup, starch paste, acacia mucilage or solutions of cellulose or polymer materials
- the powder mixture can be run through a tableting machine, giving lumps of non-uniform shape which are broken up to form granules.
- the granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting mold. The lubricated mixture is then pressed to give tablets.
- the compounds according to the disclosure can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or drypressing steps.
- a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure are provided in hard gelatin capsules. They are fabricated by producing a powder mixture as described before and filling it into shaped gelatin covers. Glidants and lubricants such as highly dispersed silica, talcum, magnesium stearate, calcium stearate or polyethylene glycol can be added to the powder mixture as solids. A disintegrant or solubilizer such as agar agar, calcium carbonate or sodium carbonate can be added likewise for improving the availability of the medication after intake of the capsule. Additionally, suitable binding agents and/or colorants can be added to the mixture, if desirable or necessary.
- Glidants and lubricants such as highly dispersed silica, talcum, magnesium stearate, calcium stearate or polyethylene glycol can be added to the powder mixture as solids.
- a disintegrant or solubilizer such as agar agar, calcium carbonate or sodium carbonate can be added likewise for improving the availability of the
- a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure are included in soft gelatin capsules (SGC).
- SGCs are dissolved on their passage through the gastrointestinal tract. They consist mainly of gelatin enriched with variable amounts of plasticizers such as glycerol or sorbitan. The release rate depends on the specific formulation of the SGC carrier material. They are also suitable for a sustained release of the active agent. SGCs are particularly useful for the administration of poorly water-soluble active agents.
- a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure are included in chewable tablets or hard caramels.
- the substance is integrated into the matrix of the tablets or caramels.
- the present application relates to 5-a m i no-2, 3-d i hydro- 1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a formulation for inhalatory administration.
- a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure reaches the patient’s alveoli. Therefore, the particle size must be sufficiently small to reach the lowest parts of the airways of the pulmonary tissue.
- the best inhalatory device class for inhalatory application of a pharmaceutically active agent are the so-called mesh nebulizers.
- Suitable commercially available mesh nebulizers, jet nebulizers, ultrasonic nebulizers, dry powder inhalers and (pressurized) metered-dose inhalers comprise, without being limiting, PARI eFlow®rapid, PARI LC STAR®, PARI Velox and PARI Velox Junior (PARI GmbH, Starnberg, Germany), Philips Respironics l-neb and Philips InnoSpire Go (Koninklijke Philips N.V., Eindhoven, Netherlands), VENTA-NEB®-ir, OPTI-NEB®, M-neb® dose + mesh nebulizer inhalation MN-300/8, M-Neb Flow+ and M-neb® mesh nebulizer MN-300/X (NEBU-TEC, Eisenfeld, Germany), Homed Deepro HCM-86C and HCM860 (HCmed Innovations Co., Ltd, Taipei, Taiwan), OMRON MicroAir LI
- the present application relates to 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a formulation for inhalatory administration, wherein the inhalatory administration is carried out by means of a vibrating mesh nebulizer.
- Mesh nebulizers can be classified into two groups according to patient interaction: Continuous mode devices and trigger-activated devices.
- Continuous mode mesh nebulizers the nebulized aerosol is continuously released into the mouthpiece and the patient has to inhale the provided aerosol.
- trigger-activated devices a defined amount of aerosol is released only upon an active and deep inspiratory breath. This way a far larger amount of active agent-containing aerosol is inhaled and reaches the lowest airways than with continuous mode devices. The latter lose a large amount of active agent-containing aerosol either to the surrounding or on the passage of the upper airways, as the aerosol release is not coupled to the respiratory cycle.
- trigger-activated mesh nebulizers are preferred, in particular vibrating mesh nebulizers.
- trigger-activated mesh nebulizers with a piezoelectric activation of the nebulization process.
- the most preferred vibrating mesh nebulizer models are high-end models such as PARI eFlow®rapid, PARI Velox, Philips Respironics l-neb, M-neb® dose + mesh nebulizer inhalation MN-300/8, Aerogen® Solo, Vectura Fox, Vectura Bayer BreelibTM.
- the mean droplet size is usually characterized as MMAD (median mass aerodynamic diameter).
- the individual droplet size is referred to as MAD (mass aerodynamic diameter). This value indicates the diameter of the nebulized particles (droplets) at which 50% are smaller or larger, respectively.
- Particles with a MMAD > 10 pm normally do not reach the lower airways, they often get stuck in the throat.
- Particles with a MMAD > 5 pm and ⁇ 10 pm usually reach the bronchi but not the alveoli.
- Particles between 100 nm and 1 pm MMAD do not deposit in the alveoli and are exhaled immediately. Therefore, the optimal range is between 1 pm and 5 pm MMAD.
- Recent publications even favor a narrower range between 3.0 pm and 4.0 pm (cf. Amirav et al. (2010) J Allergy Clin Immunol 25: 1206-1211 ; Haidl et al. (2012) Pneumologie 66: 356-360).
- a further commonly accepted quality parameter is the percentage of the particles in the generated aerosol with a diameter in the range of 1 pm to 5 pm (FPM; fine particle mass).
- FPM is a measure for the particle distribution. It is calculated by subtracting the percentage of the particles in the generated aerosol with a diameter in the range ⁇ 1 pm from the overall percentage of the particles in the generated aerosol with a diameter in the range ⁇ 5 pm (FPF; fine particle fraction).
- the present application refers also to a method for producing an aerosol according to the disclosure for the treatment of a congenital muscular dystrophy, comprising the following steps: a) filling 0.1 ml to 5 ml of an aqueous solution containing 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure and optionally at least one pharmaceutically acceptable excipient into the nebulization chamber of a mesh nebulizer, b) starting vibration of the mesh of the mesh nebulizer at a frequency of 80 kHz to 200 kHz, and c) discharging the generated aerosol at the side of the mesh of the mesh nebulizer opposite to the nebulization chamber,
- the vibration frequency of vibrating mesh nebulizers is normally in the range of 80 kHz to
- the method according to the disclosure is thus characterized in that at least 80 % in weight, preferred at least 85 % in weight, most preferred at least 90 % in weight of 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure contained in said aqueous solution are nebulized in the generated aerosol.
- the method of the invention is particularly effective in nebulizing a high percentage of the pharmaceutically active agent(s) from the provided aqueous solution during a short time.
- This is an important feature for patient compliance. A considerable percentage of the patient population finds the inhalatory process to be uncomfortable, weary and physically demanding.
- the patient’s active cooperation is essential for an effective and targeted inhalatory application. Therefore, it is desirable that a therapeutically sufficient amount is applied during a period of time as short as possible.
- time span 95 % of the substance provided in the aqueous solution could be nebulized. This is an ideal time span for a high patient compliance.
- the method according to the disclosure is thus characterized in that at least 80 % of the generated aerosol are produced during three minutes after starting nebulization in the mesh nebulizer, preferred at least 85 % and most preferred at least 90 %.
- While pharmaceutically active agents are usually provided in a single dosage container for every nebulization procedure the nebulizer and/or the mouthpiece can be used over a certain period of time and have to be replaced at certain intervals.
- a cleaning of the nebulizer and the mouthpiece is recommended by default after each nebulization. But herein patient compliance cannot be reasonably taken for granted. But even after a meticulous cleaning there are always some deposits of the aerosol in the nebulization chamber, the outlet and/or the mouthpiece. As the aerosol is produced from an aqueous solution these depositions bear the risk of producing a bioburden of bacteria that might contaminate the inhaled aerosol. Deposits may also plug holes in the mesh membrane of the mesh nebulizer. In general, the nebulizer and/or the mouthpiece should be exchanged every one or two weeks. Therefore, it is convenient to offer the medication and the nebulizer as a combined product.
- the present application refers also to a kit comprising a mesh nebulizer and a pharmaceutically acceptable container with an aqueous solution containing an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, and optionally at least one pharmaceutically acceptable excipient.
- a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure is not provided in form of an aqueous solution but in two separated containers, one for a solid form for the active agent and the other for an aqueous solution.
- the final aqueous solution is freshly prepared by solving the active agent in the final solution. Thereupon the final aqueous solution is filled into the nebulization chamber of the mesh nebulizer.
- These two containers can be completely separated containers e.g., two vials, or e.g., a dual-chamber vial.
- a membrane between the two chambers is perforated to allow for mixing of the content of both chambers.
- kits comprising a mesh nebulizer, a first pharmaceutically acceptable container with water for injection or physiological saline solution and a second pharmaceutically acceptable container with an effective dosage of a solid form of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, wherein optionally at least one pharmaceutically acceptable excipient is contained in the first pharmaceutically acceptable container and/or the second pharmaceutically acceptable container.
- the aerosol generated by the method according to the disclosure is administered, respectively self-administered by means of a mouthpiece.
- a mouthpiece can be additionally included in the beforementioned kits.
- a common way to transfer the provided aqueous solution or final aqueous solution into the nebulization chamber of the mesh nebulizer by means of a syringe equipped with an injection needle First, the aqueous solution is drawn up into the syringe and then injected into the nebulization chamber.
- a syringe and/or injection needle can be additionally included in the beforementioned kits.
- typical syringes made of polyethylene, polypropylene or cyclic olefin co-polymers can be used, and a typical gauge for a stainless-steel injection needle would be in the range of 14 to 27.
- 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, wherein said substance, composition or combination is applied in form of liposomes, micelles, multilamellar vesicles or a cyclodextrin complex.
- the present application relates to 5-ami no-2, 3-d ihydro-
- the present application also discloses the parenteral administration of 5-amino-2,3-dihydro-
- liquid dosage forms comprise solutions, suspensions and emulsions.
- examples are water and water/propylene glycol solutions for parenteral injections, or the addition of a sweetener or opacifier for oral solutions, suspensions and emulsions.
- These liquid dosage forms can be stored in vials, IV bags, ampoules, cartridges, and prefilled syringes.
- Suitable excipients include solubilizers, stabilizers, buffers, tonicity modifiers, bulking agents, viscosity enhancers/reducers, surfactants, chelating agents, and adjuvants.
- a preferred dosage form according to the invention are retard formulations i.e. , formulations with a delayed release of the at least one active agent. They are also known as sustained release (SR), extended release (ER, XR) or controlled/continuous release (CR) forms. Suitable formulations and carriers are known to a person skilled in the art (Kleinsorge (1995) Retardformulierungen in der medikamentosen Therapie. für, Levos, Levotad.
- the active agent is embedded in a matrix of insoluble substances like acrylics or chitin. Hence, the active agent must find its way out through orifices in the matrix.
- the gastric fluid attacks this porous membrane, flows in and pushes the active agent through the drilled hole on the opposite side.
- the active agent dissolves inside the matrix swelling thereupon and forming a gel. Then the active agent is released through the pores of the gel.
- Other examples include specifically coated tablets resistant to gastric fluid, retard capsules containing retard pellets of the active agent that are going to be released after the dissolution of the capsule casing, multiple unit pellet systems (MUPS), oral osmotic systems, resonates, coacervation and micro-encapsulation. With the use of such a retard formulation the release site of a drug and its pharmacokinetics can be controlled.
- a dosage form of an active agent is not dissolved before reaching a certain point of the intestines.
- the dissolution process may be engineered to be pH dependent.
- a salt of an active agent it may be preferable not to use a salt of an active agent but its neutral form.
- the present application refers also to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to the invention or a pharmaceutical composition for use according to the invention, wherein said substance or said pharmaceutical composition are formulated as a retard drug.
- a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, wherein said substance, composition or combination is formulated as a lyophilizate.
- a lyophilizate can be reconstituted with water for injection or physiological saline or a water/ethanol solution and then be administered by injection.
- Typical application forms for intravenous injections include infusion pumps, hypodermic needles, drip chambers, peripheral cannulas (peripheral venous catheters) and pressure bags.
- an aqueous solution or a physiological saline solution is preferred.
- ethanol or ethanol/water mixtures can be used.
- liquid dosage forms are drops, gels and hydrogels.
- a gel is a colloid in which the solid disperse phase forms a network in combination with that of the fluid continuous phase, resulting in a viscous semirigid sol.
- Gel properties range from soft and weak to hard and tough. They are defined as a substantially dilute cross-linked system, which exhibits no flow in the steady state. By weight, gels are mostly liquid, yet they behave like solids due to a three-dimensional cross-linked network within the liquid. It is the crosslinking within the fluid that gives a gel its consistency and contributes to the adhesive stick. Gels are a dispersion of molecules of a liquid within a solid medium.
- a hydrogel is a network of polymer chains that are hydrophilic, sometimes found as a colloidal gel in which water is the dispersion medium.
- a three-dimensional solid results from the hydrophilic polymer chains being held together by cross-links. Because of the inherent cross-links, the structural integrity of the hydrogel network does not dissolve from the high concentration of water.
- Hydrogels are highly absorbent (they can contain over 90% water) natural or synthetic polymeric networks. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content. In medicine, hydrogels can encapsulate chemical systems which upon stimulation by external factors such as a change of pH may cause specific pharmaceutically active agent(s) to be liberated to the environment, in most cases by a gel-sol transition to the liquid state.
- Suitable gel formers can be selected from the group comprising, but not limited to, agar, algin, alginic acid, bentonite, carbomer, carrageenan, hectorite, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sodium carbomer.
- the present application relates to 5-amino-2,3-dihydro- 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a formulation for sublingual tablets.
- Sublingual drug delivery can be an alternative when compared to oral drug delivery as sublingually administered dosage forms bypass hepatic metabolism. A rapid onset of pharmacological effect is often desired for some drugs, especially those used in the treatment of acute disorders.
- Sublingual tablets disintegrate rapidly, and the small amount of saliva present is usually sufficient for achieving disintegration of the dosage form coupled with better dissolution and increased bioavailability.
- the drug must be lipophilic enough to be able to partition through the lipid bilayer, but not so lipophilic such that once it is in the lipid bilayer, it will not partition out again.
- the flux across the lipid bilayer is directly proportional to the concentration gradient. Therefore, lower salivary solubility results in lower absorption rates and vice versa.
- a drug which has been formulated for sublingual should ideally have a molecular weight of less than 500 to facilitate its diffusion.
- the oral cavity has a narrow pH range which lies between 5.0 to 7.0. The inclusion of a suitable buffer during the formulation of an ionizable drug makes it possible to control the pH of aqueous saliva.
- Sweeteners, flavors, and other taste-masking agents are essential components. Sugarbased excipients quickly dissolve in saliva and produce endothermic heat of dissolution.
- Typical techniques for manufacturing sublingual tablets include direct compression, compression molding, freeze drying and hot melt extrusion (Khan et al. (2017) J Pharmaceut Res 16: 257-267).
- an administration of a pharmaceutically active agent by means of a sublingual tablet can also reach the pharynx/throat topically. Absorption of the pharmaceutically active agent occurs to a good part via the pharyngeal mucosa.
- a pharmaceutical composition comprising 5- amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscular dystrophy or Becker muscular dystrophy, is provided as a topical application form, such as creams, emulsions, lotions, gels, hydrogels, pastes, powders, ointments, liniment, films, liposomes, dermal patches, transdermal patches, transdermal sprays or suspensions.
- a topical application form such as creams, emulsions, lotions, gels, hydrogels, pastes, powders, ointments, liniment, films, liposomes, dermal patches, transdermal patches, transdermal sprays or suspensions.
- a method of treatment of a congenital muscular dystrophy in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, is disclosed, in which an effective dose of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure is administered to a patient in need thereof.
- the present disclosure refers likewise to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates for use in a method for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a subject, wherein the method comprises administering to the subject an affective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates and concomitantly or subsequently an effective amount of at least one glucocorticoid or one of its pharmaceutically acceptable salts.
- the present disclosure refers likewise to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates for use in a method for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a subject, wherein the method comprises administering to the subject an affective amount of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates and concomitantly or subsequently an effective amount of at least one glucocorticoid or one of its pharmaceutically acceptable salts, wherein 5-amino-2,3-dihydro-1 ,4-phthalazinedione is a sodium salt.
- the present disclosure refers likewise to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates for use in a method for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a subject, wherein the method comprises administering to the subject an affective amount of at least one glucocorticoid or one of its pharmaceutically acceptable salts and concomitantly or subsequently an effective amount of 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates.
- the present disclosure refers likewise to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates for use in a method for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a subject, wherein the method comprises administering to the subject an affective amount of at least one glucocorticoid or one of its pharmaceutically acceptable salts and concomitantly or subsequently an effective amount of 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates, wherein 5-amino-2,3-dihydro-1,4-phthalazinedione is a sodium salt.
- the mdx mouse model is the most widely used and investigated animal model in the research of Duchenne muscular dystrophy since the early 1980ies. These mice are characterized by muscle weakness, histological evidence of myopathy and elevated serum levels of creatin kinase (CK) (cf. Bulfield et al. (1984) PNAS 81: 1189-1192).
- CK levels are a marker of the breakdown of CK-rich tissues such as skeletal muscles (rhabdomyolysis).
- the mutation in the mdx mouse is a nonsense mutation (C-to-T transition) in exon 23 that aborts full-length dystrophin expression (cf. Sicinski et al. (1989) Science 244: 1578-1580).
- mice are indistinguishable from wild-type mice. Then skeletal muscle necrosis starts until week 6 after birth and thereupon enters in a plateau phase characterized by muscle hypertrophy. Only the diaphragm shows progressive deterioration. Severe dystrophic phenotypes such as muscle wasting, scoliosis or heart failure do not occur until mice are 15 months or older (cf. McGreevy et al. (2015) Dis Model Meeh 8: 195 - 213). Many aged mdx mice develop spontaneous sarcoma.
- IP injections were performed by restraining the mouse and delivering the treatment on either side of the abdomen, halfway between the midline and natural bend of a knee. The needle was inserted at a 45° angle, bevel side up. The syringe was aspirated slightly before the treatment is delivered to ensure a proper intraperitoneal position. Once the injection was delivered, the mouse was monitored for a couple of minutes for any adverse side effects. Animals received the injection on alternating sides daily to reduce damage from repeated injections. The oral syrup containing prednisolone was delivered to each mouse by filling the syringe (without needle tip) with the desired treatment volume.
- the syringe was checked before administration to ensure that there are no bubbles in the syrup.
- One the mouse was restrained, the syringe, without tip, was placed at the mouth of the mouse. The syringe plunger was slowly pressed allowing the mouse to lick the syrup. Once the complete treatment was delivered the mouse was placed back into its cage and monitored for a couple of minutes for any adverse side effects.
- Example 1 In vitro effects of 5-ami no-2, 3-d ihydro-1 ,4-phthalazinedione sodium salt on the contractile properties on the musculus extensor digitorum longus muscle in the mdx mouse, in comparison to deflazacort and prednisolone
- the stimulation frequency was increased in steps of 20, 30 or 50 Hz until the force reached a plateau which usually occurs around 250 Hz. This plateau was considered the maximum force (mN) generated by the muscle.
- the cross-sectional area of the muscle was measured based on muscle mass, muscle length, and tissue density.
- the muscle specific force (kN/m 2 ) was calculated based on the cross-sectional area of the muscle and was converted in relation to the individual body weight (nM/kg).
- the experimental set-up is shown in Fig. 1.
- mice could be evaluated from treatment groups 1 and 2, 14 mice from groups 3, 4, 6 and 7 and 12 mice from group 5.
- 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt showed a dose-dependent improvement of the maximum force generated by the muscle.
- the highest dose of 5-amino- 2,3-dihydro-1 ,4-phthalazinedione sodium salt (5.0 mg/kg body weight) is nearly as effective as prednisolone (106.1 ⁇ 8.0 mN/kg vs. 107.5 ⁇ 7.2 mN/kg) but much more effective than deflazacort (96.8 ⁇ 5.2 mN/kg). All data mean ⁇ SEM. In Fig. 2A these data are depicted for all treatment groups. In Fig.
- Example 2 Effects of 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt treatment on the body weight in the mdx mouse, in comparison to deflazacort and prednisolone
- glucocorticoid treatment is known to reduce the body weight of animals in experiments. This is a correlate to the effects of long-term glucocorticoid treatment in Duchenne muscular dystrophy patients (also to some degree in Becker muscular dystrophy patients) that usually develop less muscle mass and show a retarded growth in the course of the long-term treatment.
- the body weight was measured weekly starting after acclimation of the animals to the facility and the beginning of the treatment (5 weeks of age). At the start of each week the body weight of each mouse was determined on an OHAUS Scout Pro digital scale that was tared to an open 750 ml Tupperware container. Mice were constrained individually to the container and placed on top of the scale. As expected, the treatment groups with prednisolone and deflazacort (groups F and G) showed a significantly diminished body weight increase over the treatment, starting at about week 6. Roughly, the difference is about 7%. In the treatment groups with three concentrations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt no differences to the untreated mdx mice and the wild type mice could be observed over the treatment period.
- Fig. 1 Photo of the experimental set-up for the measurement of the contractile properties on the musculus extensor digitorum longus muscle in the mdx mouse as used in Example 1.
- Fig. 2 A: Bar diagram showing the effects of the different treatment groups the measurement of the contractile properties on the musculus extensor digitorum longus muscle in the mdx mouse (Example 1).
- Fig. 3 Bar diagrams of the body weight of the mice in the different treatment groups over the treatment period (weeks of age 5 - 10). wild
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the treatment of congenital muscular dystrophies, especially Duchenne muscular dystrophy or Becker muscular dystrophy. The invention relates in particular to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for said purposes. Also a pharmaceutical combination of 5-amino-2,3-dihydro-1,4- phthalazinedione or one of its pharmaceutically acceptable salts and a glucocorticoid for use in these indications is disclosed. Pharmaceutical compositions, advantageous formulation techniques and a method of treatment are disclosed.
Description
Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of congenital muscular dystrophies
FIELD OF THE INVENTION
The present invention relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the treatment of congenital muscular dystrophies, especially Duchenne muscular dystrophy or Becker muscular dystrophy. The invention relates in particular to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for said purposes. Also a pharmaceutical combination of 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts and a glucocorticoid for use in these indications is disclosed. Pharmaceutical compositions, advantageous formulation techniques and a method of treatment are disclosed.
BACKGROUND OF THE INVENTION
Congenital muscular dystrophies (CMD) encompass a wide group of muscular disorders that are characterized by a progressive skeletal muscle weakness. They display histological muscle alterations and an abnormal muscle architecture. The severity and the course of the disease is variable. Within one year of age an early onset of muscular weakness starts. Until now more than 50 forms of CMD have been described. Most of them are due to a mutation in a gene encoding for a structural protein of skeletal muscle cells (cf. Falsaperla et al. (2016) It J Pediat 42: 78). These disorders are not very common. The most prominent among them and also the most feared of is Duchenne muscular dystrophy (DMD). DMD is an X chromosome-linked recessive progressive wasting disorder caused by a loss of function mutation in the dystrophin gene. Therefore, DMD is nearly exclusively limited to boys. DMD affects approximately 1 in 5,000 male births. Progressive muscle degeneration leads to loss of ambulation at 8 - 12 years of age. Premature death occurs normally between 20 - 30 years due to respiratory and cardiac failure (cf. Guiraud and Davies (2017) Current Opinion in Pharmacology 34: 36-48). Sometimes the life span can be extended with pharmacological treatment into their thirties. Treatment options are still very limited. The most promising approach was a gene therapy in which an intact dystrophin gene should be introduced into the genome. However, it showed only very moderate success, probably due to autoimmune reactions. Another approach is exon-skipping. Herein antisense oligonucleotides are administered that should skip defect parts of the dystrophin gene thus affording the
generation of a version of dystrophin that is still truncated but halfway functional (cf. Dunckley et al. (1998) Human Mol Gen 7: 1083-1090). A moderate clinical improvement could be seen in studies with ataluren, while eteplirsen is still under clinical investigation. This method, however, requires periodic redelivery into the muscles. A systemic delivery route is still under investigation. Therefore, the standard approach is still a pharmacologic symptomatic treatment, trying to slow down the muscular deterioration thus extending the patient’s life span as long as possible. The most common prescribed drugs for DMD include glucocorticoids, above all prednisone, prednisolone and deflazacort, as well as 02 agonists such as salbutamol, anticonvulsants to control seizures and immunosuppressants.
Further approaches still under investigation are Na+/Ca2+ exchange pump inhibitors, NF-KB inhibitors, antioxidants, mitochondrial dysfunction modulators, HDAC (histone deacetylase) inhibitors, anti-fibrotic agents, myostatin inhibitors, TGF-0 pathway anti-fibrotic agents and PDE5 inhibitors against muscle ischemia (cf. Guiraud and Davies (2017) Current Opinion in Pharmacology 34: 36-48).
Until now, glucocorticoids are still the relatively best treatment. However, they entail a huge number of adverse side effects that harshly limit their long-time use. They comprise Cushing’s syndrome, hypertonia, weight gain and obesity (particularly truncal obesity, including the so called “buffalo hump”), edema, puffiness of the face (moon face), potassium loss, muscle weakness, headache, thinning of the skin, easy bruising and slow wound healing, glaucoma, cataracts, stomach and duodenum ulcers, steroid-induced diabetes, loss of control in existing diabetes, osteoporosis (resulting in bone fractures), adrenal joint necrosis (in particular of the hip or the knee joint), psychiatric disturbances (e.g. depression, euphoria, insomnia, mood swings, personality changes), psychotic behavior, growth retardation in children, convulsions, an increased rate of infections, exacerbation of opportunistic infections (such as tuberculosis, Herpes zoster and Pneumocystis pneumonia), reduced effectiveness of antibiotics and vaccines.
Mutatis mutandis this holds true for all congenital muscular dystrophies.
Thus, there is a huge medical need to find a new medication that mitigates the symptoms of CMD, particularly of Duchenne muscular dystrophy or Becker muscular dystrophy, and that improves the life quality of the patients. Ideally, it should have the same therapeutic potency as glucocorticoids in these diseases but without these strong adverse side effects in order to replace glucocorticoid treatment or to allow for a considerable reduction of glucocorticoids when combined.
Surprisingly, this task is solved by 5-amino-2,3-dihydro-1 ,4-phthalazinedione or its pharmaceutically acceptable salts.
DESCRIPTION OF THE INVENTION
5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt is tested in a mdx mouse model. These mice carry a nonsense mutation in the dystrophin gene, thus emulating a similar mutation in human Duchenne muscular dystrophy (and also Becker muscular dystrophy), as can be seen in Examples 1 and 2. It is assumed that the results in this model are predictive not only for DMD but for other congenital muscular dystrophies too.
The administration of 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt as a single drug leads to a significant improvement in physiologically relevant parameters such as muscle contractile properties and increased body weight, in comparison to control.
The comparison with therapeutic concentrations of the two widely used glucocorticoids in the treatment of DMD, prednisolone and deflazacort, showed that 5-amino-2,3-dihydro-1,4- phthalazinedione sodium salt is nearly as effective as prednisolone and much more effective than deflazacort.
5-amino-2,3-dihydro-1 ,4-phthalazinedione (luminol) belongs to the pharmaceutical class of the phthalazinediones. Compounds of this class are known for their beneficial antiinflammatory action. 5-amino-2,3-dihydro-1 ,4-phthalazinedione is also known under the name luminol. Luminol has excellent chemiluminescent properties. It is widely applied in diagnostic assays as a detection means and in forensic medicine, for example for tracing blood spots. In medicine, 5-amino-2,3-dihydro-1 ,4-phthalazinedione has been developed in the form of a sodium salt. In some countries it is approved for a broad range of acute and chronic inflammatory disorders, including a.o. acute infections of bacterial and viral origin, particularly of the intestinal tract, hepatitis B and C, gastroenteritis, inflammations such as prostatitis, endometriosis, throat inflammation, bronchial asthma, pneumonia, periodontitis, pyelonephritis and autoimmune diseases such as Crohn’s disease, ulcerative colitis, lupus erythematosus and scleroderma. Further, there is still a long list of indications in scientific and patent literature in the treatment of which 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt was allegedly tested or a beneficial use was suggested (cf. WO 2004/041169; WO 2007/018546; WO 2012/127441 ; WO 2017/202496; WO 2018/082814: a.o.).
While most conventional immunomodulatory drugs show serious adverse reactions, or are at least problematic in long-term treatment, 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts are well tolerated and have a high safety margin in respect to administered dosages.
To ensure a better solubility and bioavailability pharmaceutically acceptable salts of 5-amino- 2, 3-dihydro-1 ,4-phthalazinedione are used. Sodium, potassium and lithium salts have been described for therapeutic applications (cf. WO 2010/082858). Crystal structures for lithium,
sodium, potassium, rubidium and cesium salts were described in Guzei et al. (2013) Journal of Coordination Chemistry 66, 3722-3739. Thus, the present patent application refers also to the use of all pharmaceutically acceptable salts of 5-amino-2,3-dihydro-1 ,4-phthalazinedione.
In particular, the present application discloses 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of a congenital muscular dystrophy, wherein the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1 ,4- phthalazinedione is 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt.
5-amino-2,3-dihydro-1 ,4-phthalazinedione is often used as a hydrate, for example as sodium salt dihydrate. Thus, the present patent application refers also to the use of all hydrates and other solvates of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts may build complexes with suitable ligands. Thus, the present patent application refers also to such complexes. In the scope of the present disclosure all hydrates and solvates shall be included in the term “5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts”.
In order to ensure a reproducible and standardized API production and to provide improved stability features of an active agent anhydrous formulations are often preferred. Anhydrate forms of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt have been described as crystalline polymorphs in WO 2011/107295 (Form I, Form II) and WO 2016/096143 (Form III). These crystalline polymorphs are virtually free from phase impurities and were characterized by means of X-ray powder diffraction. This method yields a set of characteristic d-values indicating interplanar spacings [A] and of the corresponding 2-theta (20) angles [°] under which Bragg reflections occur. This yields a unique and unambiguous fingerprint of the respective polymorphs.
For Form I the following values were determined: d values: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1 ; 3.0 and/or
2-theta values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3.
Form II is characterized by the following values: d values: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and/or
2-theta values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8.
Form III yielded the following values: d values: 13.131 ; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288; 3.283;
3.222; 3.215; 3.127; 2.889 and/or
2-theta values: 6.73; 11.07; 12.31 ; 13.48; 13.59; 16.49; 22.24; 24.29; 26.14; 27.10; 27.14;
27.67; 27.72; 28.52; 30.93.
The use of anhydrous Form I of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is preferred.
5-amino-2,3-dihydro-1,4-phthalazinedione itself shows also polymorphism. A Form I (Paradies (1992) Ber. Bunsen-Ges. Phys. Chem 96: 1027-1031) and a Form II (WO 2017/140430) have been disclosed.
Thus, the present patent application refers also to the use according to the disclosure of all crystalline forms and polymorphs thereof of 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts. The use of Form II of 5-amino-2,3-dihydro-1,4- phthalazinedione is preferred.
Similar therapeutic effects are known for a variety of phthalazinediones, respectively of derivatives of 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts. An example is 6-amino-2,3-dihydrophthalazine-1, 4-dione (isoluminol). An overview of suitable phthalazinediones is given in WO 2007/018546. It is reasonable to assume that these compounds show comparable effects when being used for the therapeutic applications according to the disclosure.
Tautomerism relates to a rapid intraconversion of organic compounds in which a hydrogen atom or proton formally migrates inside the compound. This is accompanied by a switch of a single bond and adjacent double bond. The single forms are called tautomers. For example, keto-enol tautomerism occurs in 5-amino-2,3-dihydro-1,4-phthalazinedione (Proescher and Moody (1939) J Lab Clin Med, 1183-1189). Thus, the present patent application refers also to the use of all tautomers of 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts.
As used throughout the present application the term “5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts” shall encompass all beforementioned molecular variants of 5-amino-2,3-dihydro-1 ,4-phthalazinedione, i.e., 5- amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts or solvates, hydrates, crystalline polymorphs or tautomers thereof.
Unless otherwise stated, any technical or scientific term used in the present invention has the meaning that a man skilled in the relevant technical art will attribute to them.
The terms ’’composition” or ’’pharmaceutical composition” comprise at least one active ingredient in any pharmacologically acceptable defined dosage and dosage form together with at least one pharmaceutically acceptable excipient, as well as all agents that are
generated from the ingredients as outlined below directly or indirectly as a combination, accumulation, complex or crystal, or as a consequence of other reactions or interactions, as well as optionally at least one further pharmaceutical drug, as listed below.
The term “excipient” is used in this application to describe any component of a pharmaceutical composition apart of the pharmaceutically active principle. The selection of suitable excipients depends on a variety of factors, such as the dosage form, the dosage, the desired solubility and the stability of the composition.
The terms “effect”, “therapeutic effect”, “action”, “therapeutic action”, “efficacy” and “effectiveness” in regard to the substance or the pharmaceutical combination of the disclosure or any other active substance mentioned in the description refers to causally occurring beneficial consequences in the organism to which said substance has been administered before.
According to the disclosure the terms “effective amount” and “therapeutically effective amount” refer to an amount of the substance of the invention that is sufficiently large to cause a desired beneficial effect in a subject in need of such a treatment.
The terms “treatment” and “therapy” comprise the administration of at least the substance of the invention, alone or in combination with at least one further pharmaceutical drug, independently of the chronological order of the administration. Such an administration is intended to substantially improve the disease course of a congenital muscular dystrophy by stopping or decelerating the increase of disabilities during the course of the disease.
The terms “prophylaxis” or “prophylactic treatment” comprise the administration of at least the substance of the invention, alone or in combination with at least one further pharmaceutical drug, independently of the chronological order of the administration, in order to prevent or suppress the manifestation of symptoms attributed to a congenital muscular dystrophy. It refers in particular to medical conditions of a patient in which the manifestation of such symptoms is expected to occur in the far or near future with a reasonable probability.
The terms “subject” and “patient” comprise individuals suffering from disease symptoms or disabilities related to a congenital muscular dystrophy wherein said diagnosis is either approved or suspected. Individuals are mammals, in particular humans.
The term “muscular dystrophies” is not always precisely used in scientific and popular literature. Sometimes it refers also to general conditions of a wasting of muscle mass or massive weight loss, as e.g., sarcopenia, cachexia after cancer, chemotherapy or excessive fasting, dexamethasone-induced muscle wasting or age-related muscle wasting (for example in Sakuma et al. (2014) Front Aging Neurosci G 230; Saimithra et al. (2018) http://nopr.niscpr.res.in/handle/123456789/44283 ). These conditions should be better
termed “muscle atrophies”. The present disclosure relates only to muscular dystrophies in a stricter sense. To avoid any ambiguities, the term “congenital muscular dystrophies” is used throughout the present disclosure.
Congenital muscular dystrophies (CMD) comprise a heterogenous group of disorders that disrupt the function of different muscles or muscle groups. CMD become manifest with progressive muscle weakness, muscle atrophy, spasm, muscle hypertonia, and myalgias. Many CMD involve cardiac failure and respiratory dysfunction, leading to premature death. Over 800 monogenic mutations have been associated with human CMD. Most of them are associated with genes encoding for structural muscle proteins (Chemello et al. (2020) J Clin Invest 130: 2766-2776).
Duchenne muscular dystrophy (DMD) is the most common muscular hereditary disease. Prevalence ranges from 1 :3,600 to 1 :6,000. Because of the X-linked recessive inheritance nearly exclusively boys are affected. The onset of muscle weakness starts around the age of four. Disease progression is quick. Muscle loss typically occurs first in the thighs and pelvis followed by the arms. Most are unable to walk by the age of 12. Due to muscle wasting a painful malposition of the articulations and bone deformation occur. With adequate disease management patients can reach their fourth decade. At a late stage severe cardiovascular and respiratory problems will finally lead to death.
The disease is caused by a mutation in the gene for the protein dystrophin. Dystrophin is important to maintain the muscle fiber's cell membrane by linking the cell membrane with the actin filaments of the cytoskeleton. Cellular pathophysiology includes mitochondrial dysfunction, reduced ATP levels and an increased Ca2+ influx due to the damaged sarcolemma. Damaged mitochondria are not able anymore to buffer intracellular Ca2+ surges. As a compensatory mechanism, pAMPK (phosphorylated AMP-activated protein kinase) is increased as well as the number of slow fibers and utrophin. Down-regulation of nNOS (neuronal NO synthase) leads to a lack of nitric oxide. This may lead to local ischemic events due to a lack of vasodilation (cf. Heydemann (2018) Nutrients 10: 796).
Until now, there is no working causal therapy for DMD. An approach of gene therapy by which a functional dystrophin gene should be introduced into the genome was only moderately successful, as autoimmune reactions occurred. Experiments with CRISPR/Cas gene scissors are still at a very early stage. Moderate clinical improvement could be observed by exon-skipping with ataluren. Antisense oligonucleotides skip the defect part (here, a stop codon) of the dystrophin gene. The product is a truncated but partially functional dystrophin (cf. Dunckley et al. (1998) Human Mol Gen 7: 1083-1090). Until now, a periodic redelivery to the affected muscles is needed which is cumbersome and stressful for the patients.
Pharmacologic approaches for a symptomatic treatment are above all based on glucocorticoids. Prednisone, prednisolone and deflazacort are commonly prescribed. The new synthetic glucocorticoid vamorolone is still under development for DMD. The objective is to retard muscle degeneration. P2 agonists such as salbutamol are used as well as anticonvulsants to control seizures and immunosuppressants. Still in an experimental phase are Na7Ca2+ exchange pump inhibitors, NF-KB inhibitors, antioxidants, mitochondrial dysfunction modulators, HDAC (histone deacetylase) inhibitors, anti-fibrotic agents, myostatin inhibitors, TGF-0 pathway anti-fibrotic agents and PDE5 inhibitors against muscle ischemia (cf. Guiraud and Davies (2017) Current Opinion in Pharmacology 34: 36-48).
A CMD similar to DMD is Becker muscular dystrophy (BMD; synonym: Becker-Kiener muscular dystrophy). It is likewise an inherited disorder of the dystrophin gene. The associated point mutation in the dystrophin gene affords for the generation of a truncated protein, but in contrast to DMD, this truncated dystrophin is still partially working. Therefore, the disease course is milder than in DMD. Patients can often still maintain an active lifestyle. The prevalence of BMD is approximately 1.5 to 6 in 100,000 male births and thus less frequent than DMD. Symptoms usually appear around ages 8 to 25. In unfortunate disease courses patients may die at age of 40, others reach a normal age. Symptoms include typically progressive muscle weakness of the legs and the pelvis, leading to a gradual difficulty with walking. Further symptoms are upper extremity muscle weakness, toe-walking, breathing difficulties, skeletal deformities such as scoliosis, pseudohypertrophy of calf muscles, muscle cramps, heart muscle problems and elevated creatine kinase levels in blood (htpps://patient.info/doctor/beckers-muscular dystrophy, as of September 12th, 2021). There is no known cure for BMD. Physical therapy may help to mitigate the symptoms. The glucocorticoid prednisone is administered for increasing the production of the dystrophin- related protein utrophin. Because of the comparable etiology the same medications are used as in DMD.
The group of limb girdle dystrophies are associated with point mutations in the autosomally located genes encoding for a-, -, y-, 8- and e-sarcoglycanes. Sarcoglycanes are transmembrane proteins involved in the protein complex responsible for connecting the muscle fiber skeleton to the extracellular matrix. The age of onset us usually 10 to 30 years of age. Both genders are affected equally. Prevalence is about 1 : 14,500. A progressive muscle wasting occurs that affects predominantly hip and shoulder muscles. Symptoms include great difficulties in walking, bending over and squatting, Further symptoms are pseudohypertrophy, muscle hypertrophy, respiratory muscle problems, palpitation, distal muscle problems, facial muscle weakness and weak shoulder muscles. Normally, limb girdle
dystrophies do not have a fatal course. Physical therapy may help to alleviate the symptoms. Until now there is no pharmaceutical therapy. However, antioxidant therapy is suggested.
The group of dysferlinopathies encompasses myopathies caused by a mutation in the gene DYSF which encodes for dysferlin, a protein linked with skeletal muscle repair. Examples for dysferlinopathies include Miyoshi myopathy, limb girdle muscular dystrophy type 2B and distal myopathy. These diseases become usually apparent in the third of fourth decade of life. Typical symptoms are weakness and wasting of voluntary skeletal muscles such as the gastrocnemius muscle and the anterior tibial muscles. A focus of prevalence is the Middle East and the Indian subcontinent. Until now, no curative treatment exists. As therapies, synthesis of functional protein after adeno-associated virus vector transfer, gene surgery (exon skipping, trans-splicing) and pharmacological and immunological approaches are discussed. The administration of dantrolene did not turn out to improve the phenotype. Clinical trials with intravascular immunoglobulins (IV-IG) were not pursued. A candidate substance is rituximab, a monoclonal antibody directed against CD20-positive B cells (cf. Barthelemy et al. (2011) Mol Med 17: 875-882). Co-enzyme Q10 and resveratrol showed promising results in mice.
The group of GNE (bifunctional UDP-/V-acetylglucosamine 2-epimerase / N- acetylmannosamine kinase) myopathies includes hereditary inclusion body myopathy (HIBM), distal myopathy with rimmed vacuoles (DMRV), Nonaka distal myopathy and quadriceps-sparing myopathy. These mutations are most frequent in persons of Iranian Jewish descent. Muscle wasting starts around the age of 20 to 30 years, with a disease course of 10 to 15 years to disability. Symptoms include difficulty in walking on heels and in running, a weak index finger, frequent loss of balance. Until now, there is only palliative treatment, e.g. with ankle foot orthoses.
The group of spinal and bulbar muscular atrophies (SMA) encompasses SMARD1 , Werdnig- Hoffmann disease and Kugelberg-Welander disease. These disorders are characterized by a degeneration of motoneurons in the anterior horn. This is due to a mutation in the SMN1 gene that encodes for the so-called survival of motoneuron protein. It is inherited in an autosomal recessive manner. Symptoms include areflexia, particularly in the extremities, general muscle weakness, poor muscle tone, difficulties in sitting, standing and walking, weak cough and weak cry in infants, a bell-shaped torso, fasciculation of the tongue and sucking and swallowing difficulties. Pharmaceutical treatment attempts include nusinersen, an antisense nucleotide that modifies the alternative splicing of the adjuvant SMN2 gene, transgenic treatment with onasemnogene as well as risdiplam, a pyridazine derivative that also modifies the SMN2 splicing pattern. If left untreated, most infant patients do not reach the age of 4. This disease is the major course of infant death due to a genetic cause. As
there is no adequate pharmaceutical treatment, SMA patients tend to deteriorate over time. The pathophysiology includes oxidative stress. In a transgenic mouse model, the curcumin derivative ASC-JM17, a Nrf2 activator, showed to be beneficial.
Myotonic dystrophy is an autosomal hereditary disease that causes progressive muscle loss and wasting. Muscles are often unable to relax after contraction. Other common symptoms are cataracts, intellectual disability and heart conduction problems Prevalence is about 1 :8,000 worldwide. The age of onset is typically in the 20s and 30s. The disease is caused by a mutation in the DMPK gene encoding for myotonin-protein kinase (type 1 , DM1) or by a mutation is the CNBP gene encoding for cellular nuclear acid-binding protein (type 2, DM2). Currently, there is no cure for the disease. Treatments include braces or wheelchairs, pacemakers and non-invasive positive pressure ventilation. Mexiletine or carbamazepine are prescribed for muscle relaxation. Pain may be treated with tricyclic antidepressants and NSAIDs (non-steroidal anti-inflammatory drugs) (cf. Meola and Cardani (2015) Biochim Biophys Acta 1852: 594-606).
Emery-Dreyfuss muscular dystrophy (EMD) is caused by a mutation in the gene encoding for emerin. There are types EDMD1 - EDMD7. Symptoms include muscle weakness, above all in the shoulders and lower legs, shortening of the Achilles tendon and the elbow muscles, bradycardia, palpitations, contractures of the muscles. In the course of the disease patients may need orthopedics (walker, cane), physical therapy and respiratory aid. Pharmaceutical treatment is based on beta-blockers and ACE inhibitors.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by a mutation leading to a dysregulation of the gene encoding for double homeobox 4 (DUX4). In this disease, preferentially the skeletal muscles of the face, those that position the scapula and those in the upper arm, overlying the humerus are impaired (cf. Wagner (2019) Lifelong Learning in Neurology 25: 1662-1681 ). Prevalence ranges between 1 :8,000 and 1 :20,000. The disease typically becomes manifest between 15 and 30 years of age. Life expectancy is normally not reduced. No therapy could considerably slow down the progress of the disease until now. Treatment includes physical and occupational therapy as well as reconstructive surgery, if needed. Pharmaceutical treatment focuses on the glucocorticoid prednisone, the [32 agonist albuterol, the calcium channel blocker diltiazem, stamulumab (an antibody inhibiting myostatin) and the TGF-p inhibitor ACE-083.
Oculopharyngeal muscular dystrophy (OPMD) is characterized by an autosomal mutation in the gene encoding for polyadenylate-binding protein 2 (PABPN1). The onset is relatively late in life (40 - 50 years of age). Symptoms include ptosis, weakness of extraocular muscles, dysphagia, aspiration pneumonia and proximal limb weakness. Currently, no therapy exists
for stopping disease progress. Treatment attempts target specific diets and cricopharyngeal myotomy to mitigate the symptoms.
Myofibrillar myopathies (types 1 - 6, MFM1-6) are a group of clinically and genetically heterogeneous diseases of the skeletal musculature with an age of onset after 40 years of age. Clinically, slowly progressive muscle weakness with varying distribution of pareses is typical; a differentiation is made between distal, scapuloperoneal, and limb-girdle phenotypes, potentially accompanied by cardiomyopathy, pulmonary involvement, and peripheral neuropathy. Morphology reveals dissolution of myofibrils, deposition of myofibrillar degradation products, abnormal expression of numerous intramuscular proteins, and intracellular desmin-positive protein aggregates. If the heart problems and breathing problems are managed, people with MFM are expected to have a normal life expectancy. Affected genes are DES (desmin), MYOT (myotilin), LDB3 (LIM-domain binding 3, ZASP), FLNC (filamin C), CRYAB (alpha-crystalline B), BAG3 (BAG family molecular chaperone regulator 3), FHL1 (four and a half LIM domain protein 1) and DNAJB6 (DNaJ homolog subfamily B member 6). Until now there is no causal therapy for myofibrillar myopathies. If necessary, symptomatic treatment e.g. for the cardiovascular problems is used.
Further CMD encompass
- Walker-Warburg syndrome (mutation in the gene for O-mannosyltransferase 1 ; POMT1, POMT2, FCMD, FKRP), Lamin A/C-related congenital muscular dystrophy (mutation in the gene for lamin A/C; LMNA), Fukuyama congenital muscular dystrophy (mutation in the gene for fukutin; FCMD), Congenital muscular dystrophy with partial merosin deficiency, Rigid spine muscular dystrophy (mutation in the gene for selenoprotein N; SEPN 1 ), Congenital muscular dystrophy with primary laminin 2 deficiency (mutation in the gene for laminin a2; LAMA2), LARGE-related congenital muscular dystrophy (mutation in the gene for acetylglucosaminyltransferase-like protein; LARGE), Muscle-eye-brain disease (mutation in the gene for protein-O-linked mannose pi ; POMGnTI), Ullrich congenital muscular dystrophy (= Bethlem myopathy), (mutation in the gene for collagen VI; COL6A1-3), and Integrin a7 dystrophy (ITGA7).
Thus, the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscular dystrophy or Becker muscular dystrophy.
In particular, the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscular dystrophy or Becker muscular dystrophy.
In another embodiment of the invention, the present application refers to 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of a congenital muscular dystrophy that is selected from a group consisting of limb girdle dystrophies, dysferlinopathies, GNE myopathies, spinal and bulbar muscular atrophies, myotonic dystrophy, Emery-Dreyfuss muscular dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, myofibrillar myopathies, Walker-Warburg syndrome, lamin A/C-related congenital muscular dystrophy, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy with partial merosin deficiency, rigid spine muscular dystrophy, congenital muscular dystrophy with primary laminin 2 deficiency, LARGE-related congenital muscular dystrophy, muscle-eye-brain disease, Ullrich congenital muscular dystrophy, and integrin a7 dystrophy.
In another aspect of the invention the present application refers thus also to a pharmaceutical composition consisting of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy.
In particular, the present application refers thus to a pharmaceutical composition consisting of 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt and at least one glucocorticoid for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy.
In another embodiment of the invention, the present application refers to a pharmaceutical composition consisting of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one glucocorticoid for use in the treatment of a congenital muscular dystrophy that is selected from a group consisting of limb girdle dystrophies, dysferlinopathies, GNE myopathies, spinal and bulbar muscular atrophies, myotonic dystrophy, Emery-Dreyfuss muscular dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, myofibrillar myopathies, Walker-Warburg syndrome, lamin A/C-related congenital muscular dystrophy, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy with partial merosin deficiency, rigid spine
muscular dystrophy, congenital muscular dystrophy with primary laminin 2 deficiency, LARGE-related congenital muscular dystrophy, muscle-eye-brain disease, Ullrich congenital muscular dystrophy, and integrin a7 dystrophy. The use of 5-amino-2,3-dihydro-1,4- phthalazinedione in this pharmaceutical composition is preferred.
Suitable for such a pharmaceutical composition are glucocorticoids selected from a group comprising prednisone, prednisolone, deflazacort, vamorolone, flumethasone, triamcinolone acetonide, betamethasone, dexamethasone, beclomethasone, betamethasone valerate, betamethasone dipropionate, budesonide, beclomethasone dipropionate, isoflupredone, fluocinonide, fluocinolone, methylprednisolone, halcinonide, desonide, deltasone, triamcinolone, triamcinolone acetonide, tixocortol pivalate, mometasone furoate, amcinonide, fluocortolone, halometasone, alclometasone dipropionate, prednicarbate, clobetasone-17- butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, cortisol, hydrocortisone, hydrocortisone acetate, hydrocortisone-17-valerate, hydrocortisone- 17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, cortisone and cortisone acetate.
Preferred are prednisone, prednisolone, deflazacort and vamorolone.
In another aspect of the invention the present application refers to a pharmaceutical composition containing 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts or the pharmaceutical combination as defined before and at least one pharmaceutically acceptable excipient for use in the treatment of congenital muscular dystrophies.
Preferred is this pharmaceutical composition for use in the treatment of Duchenne muscular dystrophy or Becker muscular dystrophy.
The term “pharmaceutically acceptable excipient(s)” refers to natural or synthetic compounds that are added to a pharmaceutical formulation alongside the pharmaceutical active agent. They may help to bulk up the formulation, to enhance the desired pharmacokinetic properties or the stability of the formulation, as well as being beneficial in the manufacturing process. Advantageous classes of excipients according to the disclosure include, carriers, binding agents, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickening agents, pH-regulators, acidity regulators, acidifiers, solvents, isotonizing agents, disintegrants, glidants, lubricants, emulsifiers, solubilizing agents, stabilizers, diluents, anticaking agents (antiadherents), sorbents, permeation enhancers, foaming agents, antifoaming agents, opacifiers, fatliquors, consistency enhancers, hydrotropes, aromatic and flavoring substances.
In general, one or more pharmaceutically acceptable carriers are added to a pharmaceutically active agent. Eligible are all carriers known in the art and combinations thereof. In solid dosage forms they can be for example plant and animal fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talcum, zinc oxide. For liquid dosage forms and emulsions suitable carriers are for example solvents, solubilizing agents, emulsifiers such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butyl glycol, cotton seed oil, peanut oil, olive oil, castor oil, sesame oil, glycerol fatty acid esters, polyethylglycols, fatty acid esters of sorbitan. Suspensions according to the disclosure may use carriers known in the art such as diluents (e.g., water, ethanol or propylene glycol), ethoxylated isostearyl alcohols, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonites, agar agar, tragacanth.
The term binding agents refers to substances that bind powders or glue them together, rendering them cohesive through granule formation. They serve as a “glue” of the formulation. Binding agents increase the cohesive strength of the provided diluent or filler.
Suitable binding agents are for example starch from wheat, corn, rice or potato, gelatin, naturally occurring sugars such as glucose, sucrose or beta-lactose, sweeteners from corn, natural and synthetic gums such as acacia, tragacanth or ammonium calcium alginate, sodium alginate, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, magnesium aluminum silicate, waxes and others. The percentage of the binding agent in the composition can range from 1 - 30 % by weight, preferred 2 - 20 % by weight, more preferred 3 - 10 % by weight and most preferred 3 - 6 % by weight.
Colorants are excipients that bestow a colorization to the pharmaceutical formulation. These excipients can be food colorants. They can be adsorbed on a suitable adsorption means such as clay or aluminum oxide. A further advantage of a colorant is that it may visualize spilled aqueous solution on the nebulizer and/or the mouthpiece to facilitate cleaning. The amount of the colorant may vary between 0.01 and 10 % per weight of the pharmaceutical composition, preferred between 0.05 and 6 % per weight, more preferred between 0.1 and 4 % per weight, most preferred between 0.1 and 1 % per weight.
Suitable pharmaceutical colorants are for example curcumin, riboflavin, riboflavin-5’- phosphate, tartrazine, alkannin, quinolione yellow WS, Fast Yellow AB, riboflavin-5’-sodium phosphate, yellow 2G, Sunset yellow FCF, orange GGN, cochineal, carminic acid, citrus red 2, carmoisine, amaranth, Ponceau 4R, Ponceau SX, Ponceau 6R, erythrosine, red 2G, Allura red AC, Indanthrene blue RS, Patent blue V, indigo carmine, Brilliant blue FCF, chlorophylls
and chlorophyllins, copper complexes of chlorophylls and chlorophyllins, Green S, Fast Green FCF, Plain caramel, Caustic sulphite caramel, ammonia caramel, sulphite ammonia caramel, Black PN, Carbon black, vegetable carbon, Brown FK, Brown HT, alpha-carotene, beta-carotene, gamma-carotene, annatto, bixin, norbixin, paprika oleoresin, capsanthin, capsorubin, lycopene, beta-apo-8’-carotenal, ethyl ester of beta-apo-8’-carotenic acid, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, zeaxanthin, citranaxanthin, astaxanthin, betanin, anthocyanins, saffron, calcium carbonate, titanium dioxide, iron oxides, iron hydroxides, aluminum, silver, gold, pigment rubine, tannin, orcein, ferrous gluconate, ferrous lactate.
Moreover, buffer solutions are preferred for liquid formulations, in particular for pharmaceutical liquid formulations. The terms buffer, buffer system and buffer solution, in particular of an aqueous solution, refer to the capacity of the system to resist a pH change by the addition of an acid or a base, or by dilution with a solvent. Preferred buffer systems may be selected from the group comprising formate, lactate, benzoic acid, oxalate, fumarate, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinate, pyridine, phthalate, histidine, MES (2-(/V-morpholino) ethanesulfonic acid), maleic acid, cacodylate (dimethyl arsenate), carbonic acid, ADA (/V-(2-acetamido)imino diacetic acid, PIPES (4- piperazine-bis-ethanesulfonic acid), BIS-TRIS propane (1,3- bis[tris(hydroxymethyl)methylamino] propane), ethylene diamine, ACES (2-[(amino-2- oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3-(/V-morpholino) propanesulfonic acid), diethyl malonic acid, TES (2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid), HEPES (A/-2-hydroxyethylpiperazine-N’-2-ethanesulfonic acid), as well as other buffers with a pKa between 3.8 and 7.7.
Preferred are carbonic acid buffers such as acetate buffer and dicarboxylic acid buffers such as fumarate, tartrate and phthalate as well as tricarboxylic acid buffers such as citrate.
A further group of preferred buffers are inorganic buffers such as sulfate hydroxide, borate hydroxide, carbonate hydroxide, oxalate hydroxide, calcium hydroxide and phosphate buffers. Another group of preferred buffers are nitrogen-containing puffers such as imidazole, diethylene diamine and piperazine. Furthermore preferred are sulfonic acid buffers such as TES, HEPES, ACES, PIPES, [(2-hydroxy-1 ,1-bis-(hydroxymethyl)ethyl)amino]-1- propanesulfonic acid (TAPS), 4-(2-hydroxyethyl)piperazine-1 -propanesulfonic acid (EEPS), MOPS and A/,A/-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES). Another group of preferred buffers are glycine, glycyl-glycine, glycyl-glycyl-glycine, A/,/V-bis-(2- hydroxyethyl)glycine and A/-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricine). Preferred are also amino acid buffers such as glycine, alanine, valine, leucine, isoleucine,
serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxy proline, N,N,N- trimethyllysine, 3-methyl histidine, 5-hydroxy lysine, o-phosphoserine, gammacarboxyglutamate, [epsilon]-/V-acetyl lysine, [omega]-/V-methyl arginine, citrulline, ornithine and their derivatives. Particularly preferred is KH2PO4 buffer.
Preservatives for liquid and/or solid dosage forms can be used on demand. They may be selected from the group comprising, but not limited to, sorbic acid, potassium sorbate, sodium sorbate, calcium sorbate, methyl paraben, ethyl paraben, methyl ethyl paraben, propyl paraben, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, heptyl p-hydroxybenzoate, sodium methyl para-hydroxybenzoate, sodium ethyl parahydroxybenzoate, sodium propyl para-hydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohols, cresols, cetylpyridinium chloride, chlorobutanol, thiomersal (sodium 2-(ethylmercurithio) benzoic acid), sulfur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite, calcium hydrogen sulfite, potassium hydrogen sulfite, biphenyl, orthophenyl phenol, sodium orthophenyl phenol, thiabendazole, nisin, natamycin, formic acid, sodium formate, calcium formate, hexamine, formaldehyde, dimethyl dicarbonate, potassium nitrite, sodium nitrite, sodium nitrate, potassium nitrate, acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, ammonium acetate, dehydroacetic acid, sodium dehydroacetate, lactic acid, propionic acid, sodium propionate, calcium propionate, potassium propionate, boric acid, sodium tetraborate, carbon dioxide, malic acid, fumaric acid, lysozyme, copper- (ll)-sulfate, chlorine, chlorine dioxide and other suitable substances or compositions known to the person skilled in the art.
The addition of a sufficient amount of antioxidants is particularly preferable for liquid and topical dosage forms. Suitable examples for antioxidants include sodium metabisulfite, alphatocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisol, butylated hydroxytoluene, fumaric acid or propyl gallate. Preferred is the use of sodium metabisulfite, alpha-tocopherol and ascorbyl palmitate.
Tablets or pills are usually coated i.e., the coating constitutes the outer layer. This can be a film coating, a sugar coating with saccharides and a compression coating. Pharmaceutically acceptable varnishes or waxes, HPMC (hydroxypropylmethylcellulose), MC (methylcellulose) or HPC (hydroxypropylcellulose) can be used. Such a coating may help to disguise the taste, to ease the swallowing or the identification. Often plasticizers and pigments are included in the coating. Capsules normally have a gelatinous envelope that encloses the active substance(s). The specific composition and thickness of this gelatinous layer determines how
fast absorption takes place after ingestion of the capsule. Of special interest are sustained release formulations, as known in the art.
Suitable sweeteners can be selected from the group comprising mannitol, glycerol, acesulfame potassium, aspartame, cyclamate, isomalt, isomaltitol, saccharin and its sodium, potassium and calcium salts, sucralose, alitame, thaumatin, glycyrrhizin, neohesperidine dihydrochalcone, steviol glycosides, neotame, aspartame-acesulfame salt, maltitol, maltitol syrup, lactitol, xylitol, erythritol.
Suitable thickening agents can be selected from the group comprising, but not limited to, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, dextrins, polydextrose, modified starch, alkaline modified starch, bleached starch, oxidized starch, enzyme-treated starch, monostarch phosphate, distarch phosphate esterified with sodium trimetaphosphate or phosphorus oxychloride, phosphate distarch phosphate, acetylated distarch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated distarch adipate, acetylated distarch glycerol, distarch glycerin, hydroxypropyl starch, hydroxy propyl distarch glycerin, hydroxypropyl distarch phosphate, hydroxypropyl distarch glycerol, starch sodium octenyl succinate, acetylated oxidized starch, hydroxyethyl cellulose.
Suitable pH-regulators for liquid dosage forms are e.g., sodium hydroxide, hydrochloric acid, buffer substances such as sodium dihydrogen phosphate or disodium hydrogenphosphate.
Suitable acidity regulators can be selected from the group comprising acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, carbon dioxide, malic acid, fumaric acid, sodium lactate, potassium lactate, calcium lactate, ammonium lactate, magnesium lactate, citric acid, mono-, di-, trisodium citrate, mono-, di-, tripotassium citrate, mono-, di-, tricalcium citrate, tartaric acid, mono-, disodium tartrate, mono-, dipotassium tartrate, sodium potassium tartrate, ortho-phosphoric acid, lecithin citrate, magnesium citrate, ammonium malate, sodium malate, sodium hydrogen malate, calcium malate, calcium hydrogen malate, adipic acid, sodium adipate, potassium adipate, ammonium adipate, succinic acid, sodium fumarate, potassium fumarate, calcium fumarate, ammonium fumarate, 1 ,4-heptonolactone, triammonium citrate, ammonium ferric citrate, calcium glycerophosphate, isopropyl citrate, potassium carbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate, magnesium carbonate, magnesium bicarbonate, ferrous carbonate, ammonium sulfate, aluminum potassium sulfate, aluminum ammonium sulfate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium hydroxide, gluconic acid.
Acidifiers use to be inorganic chemicals that either produce or become acid. Suitable examples are ammonium chloride and calcium chloride.
Suitable solvents may be selected from the group comprising, but not limited to, water, carbonated water, water for injection, water with isotonizing agents, saline, isotonic saline, alcohols, particularly ethyl and n-butyl alcohol, and mixtures thereof.
Suitable isotonizing agents are for example pharmaceutically acceptable salts, in particular sodium chloride and potassium chloride, sugars such as glucose or lactose, sugar alcohols such as mannitol and sorbitol, citrate, phosphate, borate and mixtures thereof,
Suitable disintegrants can be selected from the group comprising starch, cold water-soluble starches such as carboxymethyl starch, cellulose derivatives such as methyl cellulose and sodium carboxymethyl cellulose, microcrystalline cellulose and cross-linked microcrystalline celluloses such as croscarmellose sodium, natural and synthetic gums such as guar, agar, karaya (Indian tragacanth), locust bean gum, tragacanth, clays such as bentonite, xanthan gum, alginates such as alginic acid and sodium alginate, foaming compositions a.o. Moisture expansion is supported by for example starch, cellulose derivatives, alginates, polysaccharides, dextrans, cross-linked polyvinyl pyrrolidone. The amount of the disintegrant in the composition may vary between 1 and 40% per weight, preferred between 3 and 20% per weight, most preferred between 5 and 10% per weight.
Glidants are materials that prevent a baking of the respective supplements and improve the flow characteristics of granulations so that the flow is smooth and constant. Suitable glidants comprise silicon dioxide, magnesium stearate, sodium stearate, starch and talcum. The amount of the glidant in the composition may vary between 0.01 and 10% per weight, preferred between 0.1 and 7% per weight, more preferred between 0.2 and 5% per weight, most preferred between 0.5 and 2% per weight.
The term “lubricants” refers to substances that are added to the dosage form in order to facilitate tablets, granulates etc. to be released from the press mold or the outlet nozzle. They diminish friction or abrasion. Lubricants are usually added shortly before pressing, as they should be present on the surface of the granules and between them and the parts of the press mold. The amount of the lubricant in the composition may vary between 0.05 and 15% per weight, preferred between 0.2 and 5% per weight, more preferred between 0.3 and 3% per weight, most preferred between 0.3 and 1.5% per weight. Suitable lubricants are a.o. sodium oleate, metal stearates such as sodium stearate, calcium stearate, potassium stearate and magnesium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, boric acid, waxes having a high melting point, polyethylene glycol.
Emulsifiers can be selected for example from the following anionic and non-ionic emulsifiers: Anionic emulsifier waxes, cetyl alcohol, cetylstearyl alcohol, stearic acid, oleic acid, polyoxyethylene polyoxypropylene block polymers, addition products of 2 to 60 mol ethylene oxide to castor oil and/or hardened castor oil, wool wax oil (lanolin), sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethene sorbitan monolaurate, polyoxyethene sorbitan monooleate, polyoxyethene sorbitan monopalmitate, polyoxyethene sorbitan monostearate, polyoxyethene sorbitan tristearate, polyoxyethene stearate, polyvinyl alcohol, metatartaric acid, calcium tartrate, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propane-1 , 2-diol alginate, carrageenan, processed Eucheuma seaweed, locust bean gum, tragacanth, acacia gum, karaya gum, gellan gum, gum ghatti, glucomannan, pectin, amidated pectin, ammonium phosphatides, brominated vegetable oil, sucrose acetate isobutyrate, glycerol esters of wood rosins, disodium phosphate, trisodium diphosphate, tetrasodium diphosphate, dicalcium diphosphate, calcium dihydrogen diphosphate, sodium triphosphate, pentapotassium triphosphate, sodium polyphosphates, sodium calcium polyphosphate, calcium polyphosphates, ammonium polyphosphate, beta-cyclodextrin, powdered cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl hydroxyethyl cellulose, croscarmellose, enzymically hydrolyzed carboxymethyl cellulose, mono- and diglycerides of fatty acids, glyceryl monostearate, glyceryl distearate, acetic acid esters of mono- and diglycerides of fatty acids, lactic acid esters of mono- and diglycerides of fatty acids, citric acid esters of mono- and diglycerides of fatty acids, tartaric acid esters of mono- and diglycerides of fatty acids, mono- and diacetyl tartaric acid esters of mono- and diglycerides of fatty acids, mixed acetic and tartaric acid esters of mono- and diglycerides of fatty acids, succinylated monoglycerides, sucrose esters of fatty acids, sucroglycerides, polyglycerol esters of fatty acids, polyglycerol polyricinoleate, propane-1 , 2-diol esters of fatty acids, propylene glycol esters of fatty acids, lactylated fatty acid esters of glycerol and propane-1 , thermally oxidized soy bean oil interacted with mono- and diglycerides of fatty acids, dioctyl sodium sulphosuccinate, sodium stearoyl-2-lactylate, calcium stearoyl-2- lactylate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate, sodium laurylsulfate, ethoxylated mono- and diglycerides, methyl glucoside-coconut oil ester, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, calcium sodium polyphosphate, calcium polyphosphate, ammonium polyphosphate, cholic acid, choline salts, distarch glycerol, starch sodium octenyl succinate, acetylated oxidized starch. Preferred are glycerin monooleate, stearic acid, phospholipids such as lecithin.
Suitable as surface-active solubilizing agents (solubilizers) are for example diethylene glycol monoethyl ester, polyethyl propylene glycol co-polymers, cyclodextrins such as a- and p- cyclodextrin, glyceryl monostearates such as Solutol HS 15 (Macrogol-15-hydroxystearate from BASF, PEG 660-15 hydroxystearates), sorbitan esters, polyoxyethylene glycol, polyoxyethylene sorbitanic acid esters, polyoxyethylene sorbitan monooleate, polyoxyethylene oxystearic acid triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, (anionic) glyceryl monooleates.
Stabilizers are substances that can be added to prevent unwanted changes. Though stabilizers are not real emulsifiers they may also contribute to the stability of emulsions. Suitable examples for stabilizers are oxystearin, xanthan gum, agar, oat gum, guar gum, tara gum, polyoxyethene stearate, aspartame-acesulfame salt, amylase, proteases, papain, bromelain, ficin, invertase, polydextrose, polyvinyl pyrrolidone, polyvinyl polypyrrolidone, triethyl citrate, maltitol, maltitol syrup.
Diluents or fillers are inactive substances added to drugs for handling minimal amounts of active agents. Examples for suitable diluents are water, mannitol, pre-gelatinized starch, starch, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate dihydrate, calcium phosphate, calcium carbonate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, xanthan gum, gum arabic or any combination thereof.
Anti-caking agents (antiadherents) can be added to a supplement or a composition of supplements for preventing the formation of lumps and for easing packaging, transport, release from the at least one chamber of the dispensing cap and consumption. Suitable examples include tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethyl siloxane.
Sorbents are materials that soak up oil from the water. Suitable examples include natural sorbents such as peat moss, sawdust, feathers, and anything else natural that contains carbon and synthetic sorbents such as polyethylene and nylon. Sorbents are used for tablet/capsule moisture-proofing by limited fluid sorbing (taking up of a liquid or a gas either by adsorption or by adsorption) in a dry state.
Permeation enhancers are often used in topical dosage forms. Suitable permeation enhancers comprise all pharmaceutically acceptable permeation enhancers known in the art, such as, without being limiting, azones such as laurocapram, 1-dodecylazacycloheptan-2-one;
sulfoxides such as dimethyl sulfoxide, DMAC, DMF; pyrrolidones such as 2-pyrrolidone, N- methyl-2-pyrrolidone; alcohols such as ethanol, 1 ,2-propandiol or decanol; glycols such as propylene glycol, diethylene glycol, tetraethylene glycol; fatty acids such as oleic acid, lauric acid, sodium lauryl sulfate, myristic acid, isopropyl myristic acid, capric acid; nonic surfactants such as polyoxyethylene-2-oleyl ether, polyoxyethylene-2-stearyl ether; terpenes; terpenoids; oxazolidinones; urea; ceramide analogs, azone analogs, menthol derivatives, etherified derivatives, esterified derivatives, transcarbams, carbamate salts, TXA derivatives, DDAIP (dodecyl 2-(dimethylamino) propanoate), DDAK, natural essential oils (all of them listed in Chen et al. (2014) Asian J. Pharm. Sc. 9, 51-64); citric acid esters such as triethyl citrate; hydrophobin polypeptides; alpha-bisabolol; dimethyl isosorbide (Arlasove® DMI); ethoxydiglycol. Preferred is 1 ,2-propandiol.
In some galenic formulations it may be desirable that a liquid oral dosage form generates some foam on being dissolved. Such an effect can be supported through the addition of a foaming agent that reduces the surface tension of the liquid, thus facilitating the formation of bubbles, or it increases its colloidal stability by inhibiting coalescence of bubbles.
Alternatively, it may stabilize foam. Suitable examples include mineral oil, quillaia extract, triethyl citrate, sodium lauryl ether sulfate, sodium lauryl sulfate, ammonium lauryl sulfate.
Alternatively, some liquid oral dosage forms may appear slightly foamy upon preparation. Though this does not interfere with the desired application it may affect patient compliance in case of a medication or the commercial success in case of dietary supplements. Therefore, it may be desirable to add a pharmaceutically acceptable anti-foaming agent (defoamer). Examples are polydimethylsiloxane or silicone oil in dietary supplements or simethicone in pharmaceuticals.
Opacifiers are substances that render the liquid dosage for, opaque, if desired. They must have a refractive index substantially different from the solvent, in most cases here water. At the same time, they should be inert to the other components of the composition. Suitable examples include titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof.
Suitable fatliquors are e.g., oleic acid decyl ester, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, sodium laurylsulfate.
Consistency enhancers are e.g., cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline waxes, non-ionic emulsifier waxes, beeswax, paraffin or stearyl alcohol.
Suitable hydrotropes are alcohols such as ethanol, isopropyl alcohol or polyols such as glycerin.
Suitable aromatic and flavoring substances comprise above all essential oils that can be used for this purpose. In general, this term refers to volatile extracts from plants or parts of plants with the respective characteristic smell. They can be extracted from plants or parts of plants by steam distillation.
Suitable examples are: Essential oils, respectively aromatic substances from achillea, sage, cedar, clove, chamomile, anise, aniseed, star anise, thyme, tea tree, peppermint, mint oil, menthol, cineol, borneol, zingerol, eucalyptus, mango, figs, lavender oil, chamomile blossoms, pine needle, cypress, orange, rose, rosewood, plum, currant, cherry, birch leaves, cinnamon, lime, grapefruit, tangerine, juniper, valerian, lemon, lemon balm, lemon grass, palmarosa, cranberry, pomegranate, rosemary, ginger, pineapple, guava, echinacea, ivy leave extract, blueberry, kaki, melon, alpha- or beta-pinene, alpha-pinene oxide, alpha- campholenic aldehyde, alpha-citronellol, alpha-isoamyl-cinnamic, alpha-cinnamic terpinene, alpha-terpineol, alpha-terpinene, aldehyde C , alpha-phellandrene, amyl cinnamic aldehyde, amyl salicylate, anisic aldehyde, basil, anethole, bay, benzyl acetate, benzyl alcohol, bergamot, bitter orange peel, black pepper, calamus, camphor, cananga oil, cardamom, carnation, carvacrol, carveol, cassia, castor, cedarwood, cinnamaldehyde, cinnamic alcohol, cis-pinane, citral, citronella, citronellal, citronellol dextro, citronellol, citronellyl acetate; citronellyl nitrile, citrus unshiu, clary sage, clove bud, coriander, corn, cotton seed, d- dihydrocarvone, decyl aldehyde, diethyl phthalate, dihydroanethole, dihydrocarveol, dihydrolinalool, dihydromyrcene, dihydromyrcenol, dihydromyrcenyl acetate; dihydroterpineol, dimethyl salicylate, dimethyloctanal, dimethyloctanol, dimethyloctanyl acetate, diphenyl oxide, dipropylene glycol, d-limonen, d-pulegone, estragole, ethyl vanillin, eucalyptol; eucalyptus citriodora, eucalyptus globulus, eugenol, evening primrose, fenchol, fennel, ferniol, fish, florazon, galaxolide, geraniol, geranium, geranyl acetate, geranyl nitrile, guaiacol, guaiacwood, gurjun balsam, heliotropin, herbanate, hiba, hydroxycitronellal, i- carvone, i-methyl acetate, ionone, isobutyl quinoleine, isobornyl acetate, isobornyl methylether, isoeugenol, isolongifolene, jasmine, lavender, limonen, linallol oxide, linallol, linalool, linalyl acetate, linseed, litsea cubeba, l-methyl acetate, longifolene, mandarin, mentha, menthane hydroperoxide, menthol crystals, menthol laevo, menthone laevo, methyl anthranilate, methyl cedryl ketone, methyl chavicol, methyl hexyl ether, methyl ionone, methyl salicylate, mineral, mint, musk ambrette, musk ketone, musk xylol, myrcene, nerol, neryl acetate, nonyl aldehyde, nutmeg, orris root, para-cymene, parahydroxy phenyl butanone crystals, patchouli, p-cymene, pennyroyal oil, pepper, perillaldehyde, petitgrain, phenyl ethyl alcohol, phenyl ethyl propionate, phenyl ethyl-2methylbutyrate, pimento berry, pimento leaf, pinane hydroperoxide, pinanol, pine ester, pine, pinene, piperonal, piperonyl acetate, piperonyl alcohol, plinol, plinyl acetate, pseudo ionone, rhodinol, rhodinyl acetate, rosalin, ryu, sandalwood, sandenol, sassafras, sesame, soybean, spearmint, spice, spike
lavender, spirantol, starflower, tea seed, terpenoid, terpineol, terpinolene, terpinyl acetate, tert-butylcyclohexyl acetate, tetrahydrolinalool, tetrahydrolinalyl acetate, tetrahydromyrcenol, thulasi, thymol, tomato, trans-2-hexenol, trans-anethole, turmeric, turpentine, vanillin, vetiver, vitalizair, white cedar, white grapefruit, Wintergreen etc. or mixtures thereof, as well as mixtures of menthol, peppermint and star anise oil or menthol and cherry flavor.
These aromatic or flavoring substances can be included in the range of 0.0001 to 10 % per weight (particularly in a composition), preferred 0.001 to 6% per weight, more preferred 0.001 to 4% per weight, most preferred 0.01 to 1% per weight, with regard to the total composition. Application- or single case-related it may be advantageous to use differing quantities.
According to the disclosure all the beforementioned excipients and classes of excipients can be used without limitation alone or in any conceivable combination thereof, as long as the inventive use is not thwarted, toxic actions may occur, or respective national legislations are infracted.
In another aspect of the invention the present application relates to 5-amino-2,3-dihydro-1,4- phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for use in a formulation for oral administration in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy.
Pharmaceutical formulations suitable for oral dosage forms of 5-amino-2,3-dihydro-1,4- phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure may be administered as separate units such as tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills; powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or in oil-in-water or water-in-oil in emulsions.
In oral dosage forms such as tablets or capsules the active agent can thus be combined with a non-toxic and pharmaceutically acceptable inert carrier such as ethanol, glycerol or water. Powders are produced by grinding the compound to a suitably tiny particle size and mixing them with a pharmaceutical carrier in a similar manner e.g., an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant or colorant can also be present.
Tablets are formulated by producing, granulating or dry pressing a powder mixture, adding a lubricant and a disintegrants and pressing the mixture to a tablet. A powder mixture is produced by mixing a suitably ground compound with a diluent or a base as described
before, and if applicable, with a binding agent such as carboxymethyl cellulose, an alginate, gelatin or polyvinyl pyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbent, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acacia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tableting machine, giving lumps of non-uniform shape which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting mold. The lubricated mixture is then pressed to give tablets. The compounds according to the disclosure can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or drypressing steps.
In another aspect of the invention 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure are provided in hard gelatin capsules. They are fabricated by producing a powder mixture as described before and filling it into shaped gelatin covers. Glidants and lubricants such as highly dispersed silica, talcum, magnesium stearate, calcium stearate or polyethylene glycol can be added to the powder mixture as solids. A disintegrant or solubilizer such as agar agar, calcium carbonate or sodium carbonate can be added likewise for improving the availability of the medication after intake of the capsule. Additionally, suitable binding agents and/or colorants can be added to the mixture, if desirable or necessary.
In another aspect of the invention 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure are included in soft gelatin capsules (SGC). SGCs are dissolved on their passage through the gastrointestinal tract. They consist mainly of gelatin enriched with variable amounts of plasticizers such as glycerol or sorbitan. The release rate depends on the specific formulation of the SGC carrier material. They are also suitable for a sustained release of the active agent. SGCs are particularly useful for the administration of poorly water-soluble active agents.
In another aspect of the invention 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure are included in chewable tablets or hard caramels. Herein the substance is integrated into the matrix of the tablets or caramels.
In another aspect of the invention the present application relates to 5-a m i no-2, 3-d i hydro- 1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a formulation for inhalatory administration.
For an effective inhalatory treatment of a congenital muscular dystrophy that at one stage of the disease course affects the respiratory organs it is advantageous that 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure reaches the patient’s alveoli. Therefore, the particle size must be sufficiently small to reach the lowest parts of the airways of the pulmonary tissue. The best inhalatory device class for inhalatory application of a pharmaceutically active agent are the so-called mesh nebulizers. In the scope of the present application practically all mesh nebulizers known in the art can be used, from rather simple single-use mesh nebulizers for cough and cold or for fancy purposes to sophisticated high-end mesh nebulizers for clinical or domestic treatment of serious diseases or conditions of the lower airways.
Suitable commercially available mesh nebulizers, jet nebulizers, ultrasonic nebulizers, dry powder inhalers and (pressurized) metered-dose inhalers comprise, without being limiting, PARI eFlow®rapid, PARI LC STAR®, PARI Velox and PARI Velox Junior (PARI GmbH, Starnberg, Germany), Philips Respironics l-neb and Philips InnoSpire Go (Koninklijke Philips N.V., Eindhoven, Netherlands), VENTA-NEB®-ir, OPTI-NEB®, M-neb® dose+ mesh nebulizer inhalation MN-300/8, M-Neb Flow+ and M-neb® mesh nebulizer MN-300/X (NEBU-TEC, Eisenfeld, Germany), Homed Deepro HCM-86C and HCM860 (HCmed Innovations Co., Ltd, Taipei, Taiwan), OMRON MicroAir LI22 and U100 (OMRON, Kyoto, Japan), Aerogen® Solo, Aerogen® Ultra and Aerogen® PRO (Aerogen, Galway, Ireland), KTMED NePlus NE-SM1 (KTMED Inc., Seoul, South Korea), Vectura Bayer Breelib™ (Bayer AG, Leverkusen, Germany), Vectura Fox, MPV Truma and MicroDrop® Smarty (MPV MEDICAL GmbH, Kirchheim, Germany), MOBI MESH (APEX Medical, New Taipei City, Taiwan), B.Well WN- 114, TH-134 and TH-135 (B.Well Swiss AG, Widnau, Switzerland), Babybelle Asia BBU01 (Babybelle Asia Ltd., Hongkong), CA-MI Kiwi and others (CA-MI sri, Langhirano, Italy), Diagnosis PRO MESH (Diagnosis S.A., Bialystok, Poland), DIGI O2 (DigiO2 International Co., Ltd., New Taipei City, Taiwan), feellife AIR PLUS, AEROCENTRE+, AIR 360+, AIR GARDEN, AIRICU, AIR MASK, AIRGEL BOY, AIR ANGEL, AIRGEL GIRL and AIR PRO 4 (Feellife Health Inc., Shenzhen, China), Hannox MA-02 (Hannox International Corp., Taipei, Taiwan), Health and Life HL100 and HL100A (HEALTH & LIFE Co., Ltd., New Taipei City,
Taiwan), Honsun NB-810B (Honsun Co., Ltd., Nantong, China), K-jump® KN-9100 (K-jump Health Co., Ltd., New Taipei City, Taiwan), microlife NEB-800 (Microlife AG, Widnau, Switzerland), OK Biotech Docspray (OK Biotech Co., Ltd., Hsinchu City, Taiwan), Prodigy Mini-Mist® (Prodigy Diabetes Care, LLC, Charlotte, USA), Quatek NM211, NE203, NE320 and NE403 (Big Eagle Holding Ltd., Taipei, Taiwan), Simzo NBM-1 and NBM-2 (Simzo Electronic Technology Ltd., Dongguan, China), Mexus® BBU01 and BBU02 (Tai Yu International Manufactory Ltd., Dongguan, China), TaiDoc TD-7001 (TaiDoc Technology Co., New Taipei City, Taiwan), Vibralung® and HIFLO Miniheart Circulaire II (Westmed Medical Group, Purchase, USA), KEJIAN (Xuzhou Kejian Hi-Tech Co., Ltd., Xuzhou, China), YM- 252, P&S-T45 and P&S-360 (TEKCELEO, Valbonne, France), Maxwell YS-31 (Maxwell India, Jaipur, India), Kernmed® JLN-MB001 (Kernmed, Durmersheim, Germany).
Preferred are mesh nebulizers with a piezoelectric activation of the nebulization process, respectively vibrating mesh nebulizers.
Thus, in another aspect of the invention the present application relates to 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a formulation for inhalatory administration, wherein the inhalatory administration is carried out by means of a vibrating mesh nebulizer.
Mesh nebulizers can be classified into two groups according to patient interaction: Continuous mode devices and trigger-activated devices. In continuous mode mesh nebulizers, the nebulized aerosol is continuously released into the mouthpiece and the patient has to inhale the provided aerosol. In trigger-activated devices a defined amount of aerosol is released only upon an active and deep inspiratory breath. This way a far larger amount of active agent-containing aerosol is inhaled and reaches the lowest airways than with continuous mode devices. The latter lose a large amount of active agent-containing aerosol either to the surrounding or on the passage of the upper airways, as the aerosol release is not coupled to the respiratory cycle.
Therefore, trigger-activated mesh nebulizers are preferred, in particular vibrating mesh nebulizers.
Particularly preferred are trigger-activated mesh nebulizers with a piezoelectric activation of the nebulization process.
Preferred are the mesh nebulizer models PARI eFlow®rapid, Philips Respironics l-neb, Philips InnoSpire Go, M-neb® dose* mesh nebulizer inhalation MN-300/8, Homed Deepro
HCM-86C and HCM860, OMRON MicroAir U100, Aerogen® Solo, KTMED NePlus NE-SM1 , Vectura Fox, Vectura Bayer Breelib™.
The most preferred vibrating mesh nebulizer models are high-end models such as PARI eFlow®rapid, PARI Velox, Philips Respironics l-neb, M-neb® dose+ mesh nebulizer inhalation MN-300/8, Aerogen® Solo, Vectura Fox, Vectura Bayer Breelib™.
The mean droplet size is usually characterized as MMAD (median mass aerodynamic diameter). The individual droplet size is referred to as MAD (mass aerodynamic diameter). This value indicates the diameter of the nebulized particles (droplets) at which 50% are smaller or larger, respectively. Particles with a MMAD > 10 pm normally do not reach the lower airways, they often get stuck in the throat. Particles with a MMAD > 5 pm and < 10 pm usually reach the bronchi but not the alveoli. Particles between 100 nm and 1 pm MMAD do not deposit in the alveoli and are exhaled immediately. Therefore, the optimal range is between 1 pm and 5 pm MMAD. Recent publications even favor a narrower range between 3.0 pm and 4.0 pm (cf. Amirav et al. (2010) J Allergy Clin Immunol 25: 1206-1211 ; Haidl et al. (2012) Pneumologie 66: 356-360).
A further commonly accepted quality parameter is the percentage of the particles in the generated aerosol with a diameter in the range of 1 pm to 5 pm (FPM; fine particle mass). FPM is a measure for the particle distribution. It is calculated by subtracting the percentage of the particles in the generated aerosol with a diameter in the range < 1 pm from the overall percentage of the particles in the generated aerosol with a diameter in the range < 5 pm (FPF; fine particle fraction).
In another aspect of the invention the present application refers also to a method for producing an aerosol according to the disclosure for the treatment of a congenital muscular dystrophy, comprising the following steps: a) filling 0.1 ml to 5 ml of an aqueous solution containing 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure and optionally at least one pharmaceutically acceptable excipient into the nebulization chamber of a mesh nebulizer, b) starting vibration of the mesh of the mesh nebulizer at a frequency of 80 kHz to 200 kHz, and c) discharging the generated aerosol at the side of the mesh of the mesh nebulizer opposite to the nebulization chamber,
The vibration frequency of vibrating mesh nebulizers is normally in the range of 80 kHz to
200 kHz, preferred 90 kHz to 180 kHz, more preferred 100 kHz to 160 kHz, most preferred
105 kHz to 130 kHz (cf. Chen, The Aerosol Society. DDL2019; Gardenshire et al. (2017) A Guide to Aerosol Delivery Devices for Respiratory Therapists, 4th ed.).
Thus, the beforementioned method is also disclosed with said vibration frequency ranges.
The method according to the disclosure is thus characterized in that at least 80 % in weight, preferred at least 85 % in weight, most preferred at least 90 % in weight of 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure contained in said aqueous solution are nebulized in the generated aerosol.
The method of the invention is particularly effective in nebulizing a high percentage of the pharmaceutically active agent(s) from the provided aqueous solution during a short time. This is an important feature for patient compliance. A considerable percentage of the patient population finds the inhalatory process to be uncomfortable, weary and physically demanding. On the other hand, the patient’s active cooperation is essential for an effective and targeted inhalatory application. Therefore, it is desirable that a therapeutically sufficient amount is applied during a period of time as short as possible. Surprisingly, it showed that during a three minutes’ time span 95 % of the substance provided in the aqueous solution could be nebulized. This is an ideal time span for a high patient compliance.
Therefore, the method according to the disclosure is thus characterized in that at least 80 % of the generated aerosol are produced during three minutes after starting nebulization in the mesh nebulizer, preferred at least 85 % and most preferred at least 90 %.
While pharmaceutically active agents are usually provided in a single dosage container for every nebulization procedure the nebulizer and/or the mouthpiece can be used over a certain period of time and have to be replaced at certain intervals. A cleaning of the nebulizer and the mouthpiece is recommended by default after each nebulization. But herein patient compliance cannot be reasonably taken for granted. But even after a meticulous cleaning there are always some deposits of the aerosol in the nebulization chamber, the outlet and/or the mouthpiece. As the aerosol is produced from an aqueous solution these depositions bear the risk of producing a bioburden of bacteria that might contaminate the inhaled aerosol. Deposits may also plug holes in the mesh membrane of the mesh nebulizer. In general, the nebulizer and/or the mouthpiece should be exchanged every one or two weeks. Therefore, it is convenient to offer the medication and the nebulizer as a combined product.
Thus, in another aspect of the invention the present application refers also to a kit comprising a mesh nebulizer and a pharmaceutically acceptable container with an aqueous solution containing an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its
pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, and optionally at least one pharmaceutically acceptable excipient.
In an alternative kit 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure is not provided in form of an aqueous solution but in two separated containers, one for a solid form for the active agent and the other for an aqueous solution. The final aqueous solution is freshly prepared by solving the active agent in the final solution. Thereupon the final aqueous solution is filled into the nebulization chamber of the mesh nebulizer. These two containers can be completely separated containers e.g., two vials, or e.g., a dual-chamber vial. For solving the active agent e.g., a membrane between the two chambers is perforated to allow for mixing of the content of both chambers.
Thus, the present application discloses also a kit, comprising a mesh nebulizer, a first pharmaceutically acceptable container with water for injection or physiological saline solution and a second pharmaceutically acceptable container with an effective dosage of a solid form of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, wherein optionally at least one pharmaceutically acceptable excipient is contained in the first pharmaceutically acceptable container and/or the second pharmaceutically acceptable container.
The aerosol generated by the method according to the disclosure is administered, respectively self-administered by means of a mouthpiece. Optionally, such a mouthpiece can be additionally included in the beforementioned kits.
A common way to transfer the provided aqueous solution or final aqueous solution into the nebulization chamber of the mesh nebulizer by means of a syringe equipped with an injection needle. First, the aqueous solution is drawn up into the syringe and then injected into the nebulization chamber. Optionally, such a syringe and/or injection needle can be additionally included in the beforementioned kits. Without being limiting, typical syringes made of polyethylene, polypropylene or cyclic olefin co-polymers can be used, and a typical gauge for a stainless-steel injection needle would be in the range of 14 to 27.
In yet another aspect of the invention 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure
or a pharmaceutical combination according to the disclosure for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, wherein said substance, composition or combination is applied in form of liposomes, micelles, multilamellar vesicles or a cyclodextrin complex.
In yet another aspect of the invention, the present application discloses 5-amino-2,3-dihydro-
1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts or a composition according to the invention or a combination according to the invention for use in the treatment a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, wherein a previous treatment with at least one other pharmaceutically active agent was refractory.
In yet another aspect of the invention, the present application discloses 5-amino-2,3-dihydro-
1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts or a composition according to the invention or a combination according to the invention for use in the treatment a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, wherein said substance or said pharmaceutical composition is formulated as a suppository.
To produce a dosage form of 5-amino-2,3-dihydro-1 ,4-phthalazinedione as a suppository, waxes with a low melting point as well as a mixture of fatty acid glycerides such as cocoa butter are first melted, then 5-amino-2,3-dihydro-1 ,4-phthalazinedione is homogenously dispersed under stirring or other mixing methods. The molten homogeneous mixture is then transferred to suitable molds and cooled down until solidification.
In yet another aspect of the invention the present application relates to 5-ami no-2, 3-d ihydro-
1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a liquid dosage form.
The present application also discloses the parenteral administration of 5-amino-2,3-dihydro-
1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in the form of intravenous injection, intraarterial injection or intraperitoneal injection.
These liquid dosage forms comprise solutions, suspensions and emulsions. Examples are water and water/propylene glycol solutions for parenteral injections, or the addition of a sweetener or opacifier for oral solutions, suspensions and emulsions.
These liquid dosage forms can be stored in vials, IV bags, ampoules, cartridges, and prefilled syringes. Suitable excipients include solubilizers, stabilizers, buffers, tonicity modifiers, bulking agents, viscosity enhancers/reducers, surfactants, chelating agents, and adjuvants.
A preferred dosage form according to the invention are retard formulations i.e. , formulations with a delayed release of the at least one active agent. They are also known as sustained release (SR), extended release (ER, XR) or controlled/continuous release (CR) forms. Suitable formulations and carriers are known to a person skilled in the art (Kleinsorge (1995) Retardformulierungen in der medikamentosen Therapie. Leipzig, Barth 8th ed.). Most commonly, the active agent is embedded in a matrix of insoluble substances like acrylics or chitin. Hence, the active agent must find its way out through orifices in the matrix. In some formulations, there is a laser-drilled hole on one side and opposite to it a porous membrane. The gastric fluid attacks this porous membrane, flows in and pushes the active agent through the drilled hole on the opposite side. In other formulations, the active agent dissolves inside the matrix swelling thereupon and forming a gel. Then the active agent is released through the pores of the gel. Other examples include specifically coated tablets resistant to gastric fluid, retard capsules containing retard pellets of the active agent that are going to be released after the dissolution of the capsule casing, multiple unit pellet systems (MUPS), oral osmotic systems, resonates, coacervation and micro-encapsulation. With the use of such a retard formulation the release site of a drug and its pharmacokinetics can be controlled. For example, it is often desirable that a dosage form of an active agent is not dissolved before reaching a certain point of the intestines. As the pH changes along the way through the intestines, the dissolution process may be engineered to be pH dependent. In therapeutic applications in which the absorption of an active agent through the intestinal mucosa shall be facilitated for increasing its bioavailability it may be preferable not to use a salt of an active agent but its neutral form.
Therefore, the present application refers also to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to the invention or a pharmaceutical composition for use according to the invention, wherein said substance or said pharmaceutical composition are formulated as a retard drug.
In yet another aspect of the invention 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, wherein said substance, composition or combination is formulated as a lyophilizate. A lyophilizate can be reconstituted with water for injection or physiological saline or a water/ethanol solution and then be administered by injection.
Typical application forms for intravenous injections include infusion pumps, hypodermic needles, drip chambers, peripheral cannulas (peripheral venous catheters) and pressure bags.
In general, an aqueous solution or a physiological saline solution is preferred. In case of a poorly soluble pharmaceutical agent according to the disclosure also ethanol or ethanol/water mixtures can be used.
Further suitable liquid dosage forms are drops, gels and hydrogels.
A gel is a colloid in which the solid disperse phase forms a network in combination with that of the fluid continuous phase, resulting in a viscous semirigid sol. Gel properties range from soft and weak to hard and tough. They are defined as a substantially dilute cross-linked system, which exhibits no flow in the steady state. By weight, gels are mostly liquid, yet they behave like solids due to a three-dimensional cross-linked network within the liquid. It is the crosslinking within the fluid that gives a gel its consistency and contributes to the adhesive stick. Gels are a dispersion of molecules of a liquid within a solid medium.
A hydrogel is a network of polymer chains that are hydrophilic, sometimes found as a colloidal gel in which water is the dispersion medium. A three-dimensional solid results from the hydrophilic polymer chains being held together by cross-links. Because of the inherent cross-links, the structural integrity of the hydrogel network does not dissolve from the high concentration of water. Hydrogels are highly absorbent (they can contain over 90% water) natural or synthetic polymeric networks. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content. In medicine, hydrogels can encapsulate chemical systems which upon stimulation by external factors such as a change of pH may cause specific pharmaceutically active agent(s) to be liberated to the environment, in most cases by a gel-sol transition to the liquid state.
Suitable gel formers can be selected from the group comprising, but not limited to, agar, algin, alginic acid, bentonite, carbomer, carrageenan, hectorite, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sodium carbomer.
In yet another aspect of the invention the present application relates to 5-amino-2,3-dihydro- 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure or a pharmaceutical combination according to the disclosure for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a formulation for sublingual tablets.
Sublingual drug delivery can be an alternative when compared to oral drug delivery as sublingually administered dosage forms bypass hepatic metabolism. A rapid onset of pharmacological effect is often desired for some drugs, especially those used in the treatment of acute disorders. Sublingual tablets disintegrate rapidly, and the small amount of saliva present is usually sufficient for achieving disintegration of the dosage form coupled with better dissolution and increased bioavailability.
The drug must be lipophilic enough to be able to partition through the lipid bilayer, but not so lipophilic such that once it is in the lipid bilayer, it will not partition out again. According to the diffusive model of absorption, the flux across the lipid bilayer is directly proportional to the concentration gradient. Therefore, lower salivary solubility results in lower absorption rates and vice versa. In general, a drug which has been formulated for sublingual should ideally have a molecular weight of less than 500 to facilitate its diffusion. The oral cavity has a narrow pH range which lies between 5.0 to 7.0. The inclusion of a suitable buffer during the formulation of an ionizable drug makes it possible to control the pH of aqueous saliva.
In order to avoid a possibly unpleasant taste or smell of the drug taste masking is needed. Sweeteners, flavors, and other taste-masking agents are essential components. Sugarbased excipients quickly dissolve in saliva and produce endothermic heat of dissolution.
They create a pleasant feeling in the mouth and are most suitable for sublingual tablets along with other flavors.
Typical techniques for manufacturing sublingual tablets include direct compression, compression molding, freeze drying and hot melt extrusion (Khan et al. (2017) J Pharmaceut Res 16: 257-267).
When swallowing is avoided, an administration of a pharmaceutically active agent by means of a sublingual tablet can also reach the pharynx/throat topically. Absorption of the pharmaceutically active agent occurs to a good part via the pharyngeal mucosa.
In yet another embodiment of the invention a pharmaceutical composition comprising 5- amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of a congenital muscular dystrophy, in particular of Duchenne muscular dystrophy or Becker muscular dystrophy, is provided as a topical application form, such as creams, emulsions, lotions, gels, hydrogels, pastes, powders, ointments, liniment, films, liposomes, dermal patches, transdermal patches, transdermal sprays or suspensions.
In a further aspect of the invention a method of treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, is disclosed, in which an effective dose of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a pharmaceutical composition according to the disclosure
or a pharmaceutical combination according to the disclosure is administered to a patient in need thereof.
The present disclosure refers likewise to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates for use in a method for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a subject, wherein the method comprises administering to the subject an affective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates and concomitantly or subsequently an effective amount of at least one glucocorticoid or one of its pharmaceutically acceptable salts.
The present disclosure refers likewise to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates for use in a method for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a subject, wherein the method comprises administering to the subject an affective amount of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates and concomitantly or subsequently an effective amount of at least one glucocorticoid or one of its pharmaceutically acceptable salts, wherein 5-amino-2,3-dihydro-1 ,4-phthalazinedione is a sodium salt.
The present disclosure refers likewise to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates for use in a method for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a subject, wherein the method comprises administering to the subject an affective amount of at least one glucocorticoid or one of its pharmaceutically acceptable salts and concomitantly or subsequently an effective amount of 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates.
The present disclosure refers likewise to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates for use in a method for the treatment of a congenital muscular dystrophy, in particular of Duchenne muscle dystrophy or Becker muscle dystrophy, in a subject, wherein the method comprises administering to the subject an affective amount of at least one glucocorticoid or one of its pharmaceutically acceptable salts and concomitantly or subsequently an effective amount of 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates, wherein 5-amino-2,3-dihydro-1,4-phthalazinedione is a sodium salt.
EXAMPLES
The mdx mouse model is the most widely used and investigated animal model in the research of Duchenne muscular dystrophy since the early 1980ies. These mice are characterized by muscle weakness, histological evidence of myopathy and elevated serum levels of creatin kinase (CK) (cf. Bulfield et al. (1984) PNAS 81: 1189-1192). Herein, CK levels are a marker of the breakdown of CK-rich tissues such as skeletal muscles (rhabdomyolysis). The mutation in the mdx mouse is a nonsense mutation (C-to-T transition) in exon 23 that aborts full-length dystrophin expression (cf. Sicinski et al. (1989) Science 244: 1578-1580). Symptoms are moderate and the mean lifespan is reduced by about 25 %. During the first two weeks after birth mdx mice are indistinguishable from wild-type mice. Then skeletal muscle necrosis starts until week 6 after birth and thereupon enters in a plateau phase characterized by muscle hypertrophy. Only the diaphragm shows progressive deterioration. Severe dystrophic phenotypes such as muscle wasting, scoliosis or heart failure do not occur until mice are 15 months or older (cf. McGreevy et al. (2015) Dis Model Meeh 8: 195 - 213). Many aged mdx mice develop spontaneous sarcoma.
Four-week-old C57BL/10ScSnJ (stock #000476) and C57BL/10ScSn-Dmdmdx/J mice (stock #001801) were sourced from Jackson Laboratory (Bar Harbor, USA). Animals were received in 2 cohorts (n=49-56; 7-8 per group). Mice were sorted into a total of five treatment groups. The mice of the control groups were wild type C57BL/10ScSnJ and the dmx strain C57BL/10ScSn-Dmdmdx/J. The animals were acclimatized upon arrival to the animal facility for 7 days, housed in cages with up to 5 mice per cage. During the study, 12-hour light/11 - hour dark cycles were maintained. Room temperature was maintained between 20°C and 23°C. Food and water were available ad libitum for the duration of the study. Mice were identified by ear tags. Randomization was done based on the average body weight of the cage. These cages were assigned randomly to treatment groups. Animals were monitored daily for changes in behavior. If necessary, a veterinarian decided whether an animal needed to be euthanized to relieve unnecessary pain or distress. In this case it was decided whether a tissue collection was yet to be performed.
The animal experiments were approved by the Dalhouse University Animal Committee in accordance with the Canadian Council on Animal Care.
All treatment compounds were administered via intraperitoneal (IP) injection, with exception of prednisolone that was delivered via oral syrup. IP injections were performed by restraining the mouse and delivering the treatment on either side of the abdomen, halfway between the midline and natural bend of a knee. The needle was inserted at a 45° angle, bevel side up. The syringe was aspirated slightly before the treatment is delivered to ensure a proper intraperitoneal position. Once the injection was delivered, the mouse was monitored for a
couple of minutes for any adverse side effects. Animals received the injection on alternating sides daily to reduce damage from repeated injections. The oral syrup containing prednisolone was delivered to each mouse by filling the syringe (without needle tip) with the desired treatment volume. The syringe was checked before administration to ensure that there are no bubbles in the syrup. One the mouse was restrained, the syringe, without tip, was placed at the mouth of the mouse. The syringe plunger was slowly pressed allowing the mouse to lick the syrup. Once the complete treatment was delivered the mouse was placed back into its cage and monitored for a couple of minutes for any adverse side effects.
The experiments were carried out by AGADA Biosciences (Halifax, Canada) on behalf of the applicant. All treatment substances were provided by the applicant. All treatment groups started with 15 mice. Treatment was blinded.
Example 1 : In vitro effects of 5-ami no-2, 3-d ihydro-1 ,4-phthalazinedione sodium salt on the contractile properties on the musculus extensor digitorum longus muscle in the mdx mouse, in comparison to deflazacort and prednisolone
Contractile properties were measured in vitro on the right musculus extensor digitorum longus (EDL) at the end of the study. The mice were anesthetized using ketamine and xylamine. The EDL muscle of the right hindlimb was removed from each mouse and immersed in individual carbogenated baths (95% O2, 5% CO2) containing Ringer’s solution (pH 7.4) at 25°C. The muscle was flanked by two electrodes. Using non-fatiguing twitches, the muscle was maintained at 10 mN for force generation. The maximal force was measured with the muscle held at 10 mN. The muscle was stimulated with an electrode to elicit tetanic contractions that are separated by 2-minute rest intervals. For the EDL with each subsequent tetanus, the stimulation frequency was increased in steps of 20, 30 or 50 Hz until the force reached a plateau which usually occurs around 250 Hz. This plateau was considered the maximum force (mN) generated by the muscle. The cross-sectional area of the muscle was measured based on muscle mass, muscle length, and tissue density. Finally, the muscle
specific force (kN/m2) was calculated based on the cross-sectional area of the muscle and was converted in relation to the individual body weight (nM/kg). The experimental set-up is shown in Fig. 1.
In this experiment, 15 mice could be evaluated from treatment groups 1 and 2, 14 mice from groups 3, 4, 6 and 7 and 12 mice from group 5.
5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt showed a dose-dependent improvement of the maximum force generated by the muscle. The highest dose of 5-amino- 2,3-dihydro-1 ,4-phthalazinedione sodium salt (5.0 mg/kg body weight) is nearly as effective as prednisolone (106.1 ± 8.0 mN/kg vs. 107.5 ± 7.2 mN/kg) but much more effective than deflazacort (96.8 ± 5.2 mN/kg). All data mean ± SEM. In Fig. 2A these data are depicted for all treatment groups. In Fig. 2B the same data are depicted as the percentual improvement of the treatment groups in comparison to the untreated mdx mice control group which was set as 100%. Herein the highest dose of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (5.0 mg/kg body weight) yielded an improvement of 16.4%, in comparison to prednisolone (18.0%) and deflazacort (6.2 %).
These data suggest that 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt is able to replace glucocorticoid treatment in Duchenne muscle dystrophy and Becker muscle dystrophy patients for obtaining the same beneficial effects but without the adverse side effects of a long-term glucocorticoid treatment. These data also suggest that a combination of 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt and a glucocorticoid would be beneficial for these patients.
Example 2: Effects of 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt treatment on the body weight in the mdx mouse, in comparison to deflazacort and prednisolone
As an adverse side effect, glucocorticoid treatment is known to reduce the body weight of animals in experiments. This is a correlate to the effects of long-term glucocorticoid treatment in Duchenne muscular dystrophy patients (also to some degree in Becker muscular dystrophy patients) that usually develop less muscle mass and show a retarded growth in the course of the long-term treatment.
The body weight was measured weekly starting after acclimation of the animals to the facility and the beginning of the treatment (5 weeks of age). At the start of each week the body weight of each mouse was determined on an OHAUS Scout Pro digital scale that was tared to an open 750 ml Tupperware container. Mice were constrained individually to the container and placed on top of the scale.
As expected, the treatment groups with prednisolone and deflazacort (groups F and G) showed a significantly diminished body weight increase over the treatment, starting at about week 6. Roughly, the difference is about 7%. In the treatment groups with three concentrations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt no differences to the untreated mdx mice and the wild type mice could be observed over the treatment period.
These data suggest that under a treatment with 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt the usually observed (and feared of) adverse side effect of less muscle mass development and retarded growth is not to be expected. In this aspect 5-amino-2,3-dihydro- 1 ,4-phthalazinedione sodium salt showed to be superior to prednisolone and deflazacort.
The development of the body weight over the treatment period is depicted for all groups in Fig. 3.
FIGURES
Fig. 1 : Photo of the experimental set-up for the measurement of the contractile properties on the musculus extensor digitorum longus muscle in the mdx mouse as used in Example 1.
Fig. 2: A: Bar diagram showing the effects of the different treatment groups the measurement of the contractile properties on the musculus extensor digitorum longus muscle in the mdx mouse (Example 1).
B: Bar diagram showing the percentual improvement of the treatment of the different treatment groups the measurement of the contractile properties on the musculus extensor digitorum longus muscle in the mdx mouse, in comparison to the untreated mdx mice (Example 1) wild
H A type vehicle
(BL10)
BB mdx vehicle
S C mdx 1.0 mg/kg 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt D mdx 2.5 mg/kg 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt
□ E mdx 5.0 mg/kg 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt
O F mdx 1.0 mg/kg prednisolone
SG mdx 1.0 mg/kg deflazacort
Fig. 3: Bar diagrams of the body weight of the mice in the different treatment groups over the treatment period (weeks of age 5 - 10). wild
O A type vehicle
(BL10)
■ B mdx vehicle
BC mdx 1.0 mg/kg 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt D mdx 2.5 mg/kg 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt
OE mdx 5.0 mg/kg 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt
O F mdx 1.0 mg/kg prednisolone
SG mdx 1.0 mg/kg deflazacort
Claims
CLAIMS 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of a congenital muscular dystrophy, wherein said congenital muscular dystrophy is Duchenne muscular dystrophy or Becker muscular dystrophy. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 1 , wherein said pharmaceutically acceptable salt is 5- amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 2, wherein 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is provided as one of crystalline anhydrate polymorph forms I, II or III characterized by crystallography values determined by means of X-ray powder diagrams: d values: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1 ; 3.0 and/or
2-theta values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3 for Form I, d values: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and/or
2-theta values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8 for Form II, and d values: 13.131 ; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288; 3.283; 3.222; 3.215; 3.127; 2.889 and/or
2-theta values: 6.73; 11.07; 12.31 ; 13.48; 13.59; 16.49; 22.24; 24.29; 26.14; 27.10; 27.14; 27.67; 27.72; 28.52; 30.93 for Form III. Pharmaceutical composition containing 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient for use in the treatment of Duchenne muscular dystrophy or Becker muscular dystrophy. Pharmaceutical composition according to claim 4, wherein said pharmaceutical composition is suitable for intravenous, oral, sublingual, inhalatory, rectal, topical or dermal administration. Pharmaceutical composition according to any one of claims 4 or 5, wherein said at least one pharmaceutically acceptable excipient is selected from a group comprising
carriers, binding agents, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickening agents, pH-regulators, acidity regulators, acidifiers, solvents, isotonizing agents, disintegrants, glidants, lubricants, emulsifiers, solubilizing agents, stabilizers, diluents, anti-caking agents, sorbents, permeation enhancers, foaming agents, anti-foaming agents, opacifiers, fatliquors, consistency enhancers, hydrotropes, aromatic and flavoring substances. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 1 or a pharmaceutical composition for use according to claim 5, wherein said substance or said pharmaceutical composition is applied orally in the form of tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills; powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or in oil-in-water or water- in-oil in emulsions. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 1 or a pharmaceutical composition for use according to claim 5, wherein said substance or said pharmaceutical composition is applied in the form of sublingual tablets or lozenges. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 1 or a pharmaceutical composition for use according to claim 5, wherein said substance or said pharmaceutical composition is applied by inhalation by using a vibrant mesh nebulizer, metered dose-inhaler, jet nebulizer or dry-powder inhaler. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 1 or a pharmaceutical composition for use according to claim 5, wherein said substance or said pharmaceutical composition is formulated as a retard drug. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 1 or a pharmaceutical composition for use according to claim 5, wherein said substance or said pharmaceutical composition is formulated as a lyophilizate. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 1 or a pharmaceutical composition for use according to
claim 5, wherein said substance or said pharmaceutical composition is applied in form of liposomes, micelles, multilamellar vesicles or a cyclodextrin complex. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 1 or a pharmaceutical composition for use according to claim 5, wherein a previous treatment with at least one other pharmaceutically active agent was refractory. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 1 or a pharmaceutical composition for use according to claim 5, wherein said substance or said pharmaceutical composition is formulated as a suppository. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 1 or a pharmaceutical composition for use according to claim 5, wherein said substance or said pharmaceutical composition is applied topically in the form of creams, emulsions, lotions, gels, hydrogels, pastes, powders, ointments, liniment, films, liposomes, dermal patches, transdermal patches, transdermal sprays or suspensions.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA3240892A CA3240892A1 (en) | 2022-01-07 | 2023-01-05 | Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of congenital muscular dystrophies |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP22000008.7 | 2022-01-07 | ||
EP22000008 | 2022-01-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023131579A1 true WO2023131579A1 (en) | 2023-07-13 |
Family
ID=79287836
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2023/000002 WO2023131579A1 (en) | 2022-01-07 | 2023-01-05 | Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of congenital muscular dystrophies |
Country Status (2)
Country | Link |
---|---|
CA (1) | CA3240892A1 (en) |
WO (1) | WO2023131579A1 (en) |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6953799B1 (en) * | 2002-10-30 | 2005-10-11 | Bach Pharma, Inc. | Modulation of cell fates and activities by diketo phthalazines |
US20090018137A1 (en) * | 2002-10-30 | 2009-01-15 | Bach Pharma, Inc. | Modulation of cell fates and activities by phthalazinediones |
WO2017202496A1 (en) * | 2016-05-26 | 2017-11-30 | Metriopharm Ag | Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of inflammatory and/or degenerative disorders of the ligaments of the joints, articular capsules and bursae |
JP2017537958A (en) * | 2014-12-18 | 2017-12-21 | メトリオファーム アーゲー | Crystalline form of 5-amino-2,3-dihydrophthalazine 1,4-dione sodium salt, pharmaceutical preparation containing the same, and process for producing this form |
US20200369624A1 (en) * | 2016-02-16 | 2020-11-26 | Metriopharm Ag | Crystalline form of 5-amino-2, 3-dihydrophthalazine-1, 4-dione |
US20210315873A1 (en) * | 2020-04-13 | 2021-10-14 | The Research Foundation For The State University Of New York | Method of treatment for prevention of glucocorticoid toxicity and/or enhancement of muscle regeneration via neutrophil elastase inhibition |
WO2021249667A1 (en) * | 2020-06-10 | 2021-12-16 | Metriopharm Ag | Compound for the treatment of coronaviral infections |
WO2022008093A1 (en) * | 2020-07-09 | 2022-01-13 | Metriopharm Ag | Glucocorticoid-sparing agent |
-
2023
- 2023-01-05 WO PCT/EP2023/000002 patent/WO2023131579A1/en unknown
- 2023-01-05 CA CA3240892A patent/CA3240892A1/en active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6953799B1 (en) * | 2002-10-30 | 2005-10-11 | Bach Pharma, Inc. | Modulation of cell fates and activities by diketo phthalazines |
US20090018137A1 (en) * | 2002-10-30 | 2009-01-15 | Bach Pharma, Inc. | Modulation of cell fates and activities by phthalazinediones |
JP2017537958A (en) * | 2014-12-18 | 2017-12-21 | メトリオファーム アーゲー | Crystalline form of 5-amino-2,3-dihydrophthalazine 1,4-dione sodium salt, pharmaceutical preparation containing the same, and process for producing this form |
US20200369624A1 (en) * | 2016-02-16 | 2020-11-26 | Metriopharm Ag | Crystalline form of 5-amino-2, 3-dihydrophthalazine-1, 4-dione |
WO2017202496A1 (en) * | 2016-05-26 | 2017-11-30 | Metriopharm Ag | Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of inflammatory and/or degenerative disorders of the ligaments of the joints, articular capsules and bursae |
US20210315873A1 (en) * | 2020-04-13 | 2021-10-14 | The Research Foundation For The State University Of New York | Method of treatment for prevention of glucocorticoid toxicity and/or enhancement of muscle regeneration via neutrophil elastase inhibition |
WO2021249667A1 (en) * | 2020-06-10 | 2021-12-16 | Metriopharm Ag | Compound for the treatment of coronaviral infections |
WO2022008093A1 (en) * | 2020-07-09 | 2022-01-13 | Metriopharm Ag | Glucocorticoid-sparing agent |
Non-Patent Citations (1)
Title |
---|
MESA L E ET AL: "Steroids in duchenne muscular dystrophy - Deflazacort trial", NEUROMUSCULAR DISORDERS, ELSEVIER LTD, GB, vol. 1, no. 4, 1 January 1991 (1991-01-01), pages 261 - 266, XP024402868, ISSN: 0960-8966, [retrieved on 19910101], DOI: 10.1016/0960-8966(91)90099-E * |
Also Published As
Publication number | Publication date |
---|---|
CA3240892A1 (en) | 2023-07-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2017202496A1 (en) | Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of inflammatory and/or degenerative disorders of the ligaments of the joints, articular capsules and bursae | |
US20230218614A1 (en) | Compound for the treatment of coronaviral infections | |
TW201109051A (en) | Compositions, methods and systems for respiratory delivery of two or more active agents | |
TW200916126A (en) | Organic compounds | |
WO2009046444A2 (en) | Formulation for intranasal administration of diazepam | |
EP4125802A1 (en) | 5-amino-2,3-dihydro-1,4-phthalazinedione for treatment of acute lung injury | |
JP2023517532A (en) | Treatment with powdered intranasal epinephrine | |
JP2022521319A (en) | Minimize suspension aeration during in-line mixing | |
US20240075029A1 (en) | Luminol for the prophylaxis and the treatment of sequelae of a sars-cov-2 infection | |
Xu et al. | Intranasal co-delivery of berberine and evodiamine by self-assembled thermosensitive in-situ hydrogels for improving depressive disorder | |
WO2023131579A1 (en) | Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of congenital muscular dystrophies | |
RU2582218C2 (en) | Method for preparing metered dose sprayed inhaler for treating respiratory disease | |
BR112018074551B1 (en) | PHARMACEUTICAL AEROSOL, LIQUID AND SOLID PHARMACEUTICAL COMPOSITIONS, KIT, E, METHOD TO PREPARE AND DISPENSE AN AEROSOL | |
Natalini et al. | The influence of surfactant on the properties of albendazole-bile salts particles designed for lung delivery | |
KR20100065360A (en) | Dheas inhalation compositions | |
TWI332403B (en) | ||
Tai et al. | Spray freeze dried cannabidiol with dipalmitoylphosphatidylcholine (DPPC) for inhalation and solubility enhancement | |
EP3981405A1 (en) | Compound for the treatment of coronaviral infections | |
WO2023131578A1 (en) | Combination of budesonide and 5-amino-2,3-dihydro-1,4-phthalazinedione | |
WO2023104327A1 (en) | Combination of 5-amino-2,3-dihydro-1,4-phtalazinedione and a 6'-methoxycinchonan-9-ol for use in the treatment of coronaviral infections | |
WO2023179905A1 (en) | Combination of 5-amino-2,3-dihydro-1,4-phthalazinedione and a fumaric acid ester | |
TW201717936A (en) | Composition for nebulizer | |
JP2023503380A (en) | Peptides and their use in treating inflammation | |
SAIGAL | CONTROLLED RELEASE INHALABLE POLYMERIC MICROSPHERES FOR TREATMENT OF PULMONARY HYPERTENSION | |
WO2003002095A1 (en) | O/w type microemulsion preparation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23702218 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 3240892 Country of ref document: CA |